diff --git a/CMakeLists.txt b/CMakeLists.txt
index 4d9656c4060..e0a20f9030e 100644
--- a/CMakeLists.txt
+++ b/CMakeLists.txt
@@ -1631,32 +1631,16 @@ if(FIRST_RUN)
   endif()
 endif()
 
-# set the endian define
-if(MSVC)
-  # For some reason this fails on MSVC.
-  add_definitions(-D__LITTLE_ENDIAN__)
-
-  # OSX-Note: as we do cross-compiling with specific set architecture,
-  # endianness-detection and auto-setting is counterproductive
-  # so we just set endianness according CMAKE_OSX_ARCHITECTURES
-
-elseif(CMAKE_OSX_ARCHITECTURES MATCHES i386 OR
-       CMAKE_OSX_ARCHITECTURES MATCHES x86_64 OR
-       CMAKE_OSX_ARCHITECTURES MATCHES arm64)
-  add_definitions(-D__LITTLE_ENDIAN__)
-elseif(CMAKE_OSX_ARCHITECTURES MATCHES ppc OR CMAKE_OSX_ARCHITECTURES MATCHES ppc64)
-  add_definitions(-D__BIG_ENDIAN__)
-
+# Test endianness and set the endian define.
+include(TestBigEndian)
+test_big_endian(_SYSTEM_BIG_ENDIAN)
+if(_SYSTEM_BIG_ENDIAN)
+  message(FATAL_ERROR "Blender does not support building on Big Endian systems" )
 else()
-  include(TestBigEndian)
-  test_big_endian(_SYSTEM_BIG_ENDIAN)
-  if(_SYSTEM_BIG_ENDIAN)
-    add_definitions(-D__BIG_ENDIAN__)
-  else()
-    add_definitions(-D__LITTLE_ENDIAN__)
-  endif()
-  unset(_SYSTEM_BIG_ENDIAN)
+  add_definitions(-D__LITTLE_ENDIAN__)
 endif()
+unset(_SYSTEM_BIG_ENDIAN)
+
 if(WITH_IMAGE_OPENJPEG)
   # Special handling of Windows platform where openjpeg is always static.
   if(WIN32)
diff --git a/intern/guardedalloc/intern/mallocn_guarded_impl.cc b/intern/guardedalloc/intern/mallocn_guarded_impl.cc
index 1a5fae39ae9..966be293d07 100644
--- a/intern/guardedalloc/intern/mallocn_guarded_impl.cc
+++ b/intern/guardedalloc/intern/mallocn_guarded_impl.cc
@@ -174,11 +174,8 @@ static const char *check_memlist(const MemHead *memh);
 /* locally used defines                                                  */
 /* --------------------------------------------------------------------- */
 
-#ifdef __BIG_ENDIAN__
-#  define MAKE_ID(a, b, c, d) (int(a) << 24 | int(b) << 16 | (c) << 8 | (d))
-#else
-#  define MAKE_ID(a, b, c, d) (int(d) << 24 | int(c) << 16 | (b) << 8 | (a))
-#endif
+/* NOTE: this is endianness-sensitive. */
+#define MAKE_ID(a, b, c, d) (int(d) << 24 | int(c) << 16 | (b) << 8 | (a))
 
 #define MEMTAG1 MAKE_ID('M', 'E', 'M', 'O')
 #define MEMTAG2 MAKE_ID('R', 'Y', 'B', 'L')
diff --git a/release/datafiles/userdef/userdef_default_theme.c b/release/datafiles/userdef/userdef_default_theme.c
index 38a082b7e54..72a15a5dda9 100644
--- a/release/datafiles/userdef/userdef_default_theme.c
+++ b/release/datafiles/userdef/userdef_default_theme.c
@@ -14,13 +14,9 @@
 
 /* clang-format off */
 
-#ifdef __LITTLE_ENDIAN__
-#  define RGBA(c) {((c) >> 24) & 0xff, ((c) >> 16) & 0xff, ((c) >> 8) & 0xff, (c) & 0xff}
-#  define RGB(c)  {((c) >> 16) & 0xff, ((c) >> 8) & 0xff, (c) & 0xff}
-#else
-#  define RGBA(c) {(c) & 0xff, ((c) >> 8) & 0xff, ((c) >> 16) & 0xff, ((c) >> 24) & 0xff}
-#  define RGB(c)  {(c) & 0xff, ((c) >> 8) & 0xff, ((c) >> 16) & 0xff}
-#endif
+/* NOTE: this is endianness-sensitive. */
+#define RGBA(c) {((c) >> 24) & 0xff, ((c) >> 16) & 0xff, ((c) >> 8) & 0xff, (c) & 0xff}
+#define RGB(c)  {((c) >> 16) & 0xff, ((c) >> 8) & 0xff, (c) & 0xff}
 
 const bTheme U_theme_default = {
   .name = "Default",
diff --git a/source/blender/blendthumb/src/blendthumb.hh b/source/blender/blendthumb/src/blendthumb.hh
index 628da011958..df2d14daa09 100644
--- a/source/blender/blendthumb/src/blendthumb.hh
+++ b/source/blender/blendthumb/src/blendthumb.hh
@@ -45,10 +45,5 @@ std::optional<blender::Vector<uint8_t>> blendthumb_create_png_data_from_thumb(
 eThumbStatus blendthumb_create_thumb_from_file(FileReader *rawfile, Thumbnail *thumb);
 
 /* INTEGER CODES */
-#ifdef __BIG_ENDIAN__
-/* Big Endian */
-#  define MAKE_ID(a, b, c, d) ((int)(a) << 24 | (int)(b) << 16 | (c) << 8 | (d))
-#else
-/* Little Endian */
-#  define MAKE_ID(a, b, c, d) ((int)(d) << 24 | (int)(c) << 16 | (b) << 8 | (a))
-#endif
+/* NOTE: this is endianness-sensitive. */
+#define MAKE_ID(a, b, c, d) ((int)(d) << 24 | (int)(c) << 16 | (b) << 8 | (a))
diff --git a/source/blender/blendthumb/src/blendthumb_extract.cc b/source/blender/blendthumb/src/blendthumb_extract.cc
index 74acf23fb4a..a8711151e11 100644
--- a/source/blender/blendthumb/src/blendthumb_extract.cc
+++ b/source/blender/blendthumb/src/blendthumb_extract.cc
@@ -14,7 +14,6 @@
 
 #include "BLI_alloca.h"
 #include "BLI_endian_defines.h"
-#include "BLI_endian_switch.h"
 #include "BLI_fileops.h"
 #include "BLI_filereader.h"
 #include "BLI_string.h"
@@ -24,6 +23,8 @@
 
 #include "blendthumb.hh"
 
+BLI_STATIC_ASSERT(ENDIAN_ORDER == L_ENDIAN, "Blender only builds on little endian systems")
+
 static void thumb_data_vertical_flip(Thumbnail *thumb)
 {
   uint32_t *rect = (uint32_t *)thumb->data.data();
@@ -43,13 +44,12 @@ static void thumb_data_vertical_flip(Thumbnail *thumb)
   free(line);
 }
 
-static int32_t bytes_to_native_i32(const uint8_t bytes[4], bool endian_switch)
+static int32_t bytes_to_native_i32(const uint8_t bytes[4])
 {
   int32_t data;
   memcpy(&data, bytes, 4);
-  if (endian_switch) {
-    BLI_endian_switch_int32(&data);
-  }
+  /* NOTE: this is endianness-sensitive. */
+  /* PNG is always little-endian, and would require switching on a big-endian system. */
   return data;
 }
 
@@ -84,12 +84,11 @@ static eThumbStatus blendthumb_extract_from_file_impl(FileReader *file,
                                                       Thumbnail *thumb,
                                                       const BlenderHeader &header)
 {
-  const bool endian_switch = header.endian != ENDIAN_ORDER;
+  BLI_assert(header.endian == L_ENDIAN);
   /* Iterate over file blocks until we find the thumbnail or run out of data. */
   while (true) {
     /* Read next BHead. */
-    const std::optional<BHead> bhead = BLO_readfile_read_bhead(
-        file, header.bhead_type(), endian_switch);
+    const std::optional<BHead> bhead = BLO_readfile_read_bhead(file, header.bhead_type());
     if (!bhead.has_value()) {
       /* File has ended. */
       return BT_INVALID_THUMB;
@@ -104,8 +103,8 @@ static eThumbStatus blendthumb_extract_from_file_impl(FileReader *file,
         if (!file_read(file, shape, sizeof(shape))) {
           return BT_INVALID_THUMB;
         }
-        thumb->width = bytes_to_native_i32(&shape[0], endian_switch);
-        thumb->height = bytes_to_native_i32(&shape[4], endian_switch);
+        thumb->width = bytes_to_native_i32(&shape[0]);
+        thumb->height = bytes_to_native_i32(&shape[4]);
 
         /* Verify that image dimensions and data size make sense. */
         size_t data_size = bhead->len - sizeof(shape);
@@ -190,6 +189,13 @@ eThumbStatus blendthumb_create_thumb_from_file(FileReader *rawfile, Thumbnail *t
     return BT_EARLY_VERSION;
   }
 
+  /* Check if the file was written from a big-endian build. */
+  if (header.endian != L_ENDIAN) {
+    file->close(file);
+    return BT_INVALID_FILE;
+  }
+  BLI_assert(header.endian == ENDIAN_ORDER);
+
   /* Read the thumbnail. */
   eThumbStatus err = blendthumb_extract_from_file_impl(file, thumb, header);
   file->close(file);
diff --git a/source/blender/blendthumb/src/blendthumb_png.cc b/source/blender/blendthumb/src/blendthumb_png.cc
index 4b979fd776a..89f6e1d81c4 100644
--- a/source/blender/blendthumb/src/blendthumb_png.cc
+++ b/source/blender/blendthumb/src/blendthumb_png.cc
@@ -21,9 +21,9 @@
 
 static void png_extend_native_int32(blender::Vector<uint8_t> &output, int32_t data)
 {
-  if (ENDIAN_ORDER == L_ENDIAN) {
-    BLI_endian_switch_int32(&data);
-  }
+  /* NOTE: this is endianness-sensitive. */
+  /* PNG is big-endian, its values need to be switched on little-endian systems. */
+  BLI_endian_switch_int32(&data);
   output.extend_unchecked(blender::Span((uint8_t *)&data, 4));
 }
 
diff --git a/source/blender/blenkernel/intern/action.cc b/source/blender/blenkernel/intern/action.cc
index 8e362743d31..44c67fc4797 100644
--- a/source/blender/blenkernel/intern/action.cc
+++ b/source/blender/blenkernel/intern/action.cc
@@ -24,7 +24,6 @@
 #include "DNA_object_types.h"
 #include "DNA_scene_types.h"
 
-#include "BLI_endian_switch.h"
 #include "BLI_ghash.h"
 #include "BLI_listbase.h"
 #include "BLI_math_color.h"
@@ -671,12 +670,11 @@ static void read_slots(BlendDataReader *reader, animrig::Action &action)
   for (int i = 0; i < action.slot_array_num; i++) {
     BLO_read_struct(reader, ActionSlot, &action.slot_array[i]);
 
-    /* Undo generic endian switching, as the ID type values are not numerically the same between
-     * little and big endian machines. Due to the way they are defined, they are always in the same
-     * byte order, regardless of hardware/platform endianness. */
-    if (BLO_read_requires_endian_switch(reader)) {
-      BLI_endian_switch_int16(&action.slot_array[i]->idtype);
-    }
+    /* NOTE: this is endianness-sensitive. */
+    /* In case of required endian switching, this code would have to undo the generic endian
+     * switching, as the ID type values are not numerically the same between little and big endian
+     * machines. Due to the way they are defined, they are always in the same byte order,
+     * regardless of hardware/platform endianness. */
 
     action.slot_array[i]->wrap().blend_read_post();
   }
@@ -686,12 +684,10 @@ static void action_blend_read_data(BlendDataReader *reader, ID *id)
 {
   animrig::Action &action = reinterpret_cast<bAction *>(id)->wrap();
 
-  /* Undo generic endian switching (careful, only the two least significant bytes of the int32 must
-   * be swapped back here, since this value is actually an int16). */
-  if (BLO_read_requires_endian_switch(reader)) {
-    bAction *act = reinterpret_cast<bAction *>(id);
-    BLI_endian_switch_int16(reinterpret_cast<short *>(&act->idroot));
-  }
+  /* NOTE: this is endianness-sensitive. */
+  /* In case of required endianness switching, this code would need to undo the generic endian
+   * switching (careful, only the two least significant bytes of the int32 must be swapped back
+   * here, since this value is actually an int16). */
 
   read_strip_keyframe_data_array(reader, action);
   read_layers(reader, action);
diff --git a/source/blender/blenkernel/intern/bake_items_serialize.cc b/source/blender/blenkernel/intern/bake_items_serialize.cc
index 99aa33c54fd..1150be710c0 100644
--- a/source/blender/blenkernel/intern/bake_items_serialize.cc
+++ b/source/blender/blenkernel/intern/bake_items_serialize.cc
@@ -15,7 +15,6 @@
 #include "BKE_volume.hh"
 
 #include "BLI_endian_defines.h"
-#include "BLI_endian_switch.h"
 #include "BLI_listbase.h"
 #include "BLI_math_matrix_types.hh"
 #include "BLI_path_utils.hh"
@@ -289,11 +288,8 @@ std::optional<ImplicitSharingInfoAndData> BlobReadSharing::read_shared(
 
 static StringRefNull get_endian_io_name(const int endian)
 {
-  if (endian == L_ENDIAN) {
-    return "little";
-  }
-  BLI_assert(endian == B_ENDIAN);
-  return "big";
+  BLI_assert(endian == L_ENDIAN);
+  return "little";
 }
 
 static StringRefNull get_domain_io_name(const AttrDomain domain)
@@ -329,7 +325,7 @@ static std::optional<eCustomDataType> get_data_type_from_io_name(const StringRef
 }
 
 /**
- * Write the data and remember which endianness the data had.
+ * Write the data, always in little endian.
  */
 static std::shared_ptr<DictionaryValue> write_blob_raw_data_with_endian(
     BlobWriter &blob_writer,
@@ -338,14 +334,14 @@ static std::shared_ptr<DictionaryValue> write_blob_raw_data_with_endian(
     const int64_t size_in_bytes)
 {
   auto io_data = blob_sharing.write_deduplicated(blob_writer, data, size_in_bytes);
-  if (ENDIAN_ORDER == B_ENDIAN) {
-    io_data->append_str("endian", get_endian_io_name(ENDIAN_ORDER));
-  }
+  BLI_STATIC_ASSERT(ENDIAN_ORDER == L_ENDIAN, "Blender only builds on little endian systems")
   return io_data;
 }
 
 /**
- * Read data of an into an array and optionally perform an endian switch if necessary.
+ * Read data of an into an array.
+ *
+ * \returns True if sucessful, false if reading fails, or endian switch would be needed.
  */
 [[nodiscard]] static bool read_blob_raw_data_with_endian(const BlobReader &blob_reader,
                                                          const DictionaryValue &io_data,
@@ -367,21 +363,9 @@ static std::shared_ptr<DictionaryValue> write_blob_raw_data_with_endian(
   const StringRefNull current_endian = get_endian_io_name(ENDIAN_ORDER);
   const bool need_endian_switch = stored_endian != current_endian;
   if (need_endian_switch) {
-    switch (element_size) {
-      case 1:
-        break;
-      case 2:
-        BLI_endian_switch_uint16_array(static_cast<uint16_t *>(r_data), elements_num);
-        break;
-      case 4:
-        BLI_endian_switch_uint32_array(static_cast<uint32_t *>(r_data), elements_num);
-        break;
-      case 8:
-        BLI_endian_switch_uint64_array(static_cast<uint64_t *>(r_data), elements_num);
-        break;
-      default:
-        return false;
-    }
+    /* NOTE: this is endianness-sensitive. */
+    /* Blender only builds on little endian systems, and reads little endian data here. */
+    return false;
   }
   return true;
 }
diff --git a/source/blender/blenkernel/intern/customdata_file.cc b/source/blender/blenkernel/intern/customdata_file.cc
index c39f70dc08a..d2a1a3aa3ed 100644
--- a/source/blender/blenkernel/intern/customdata_file.cc
+++ b/source/blender/blenkernel/intern/customdata_file.cc
@@ -13,7 +13,6 @@
 #include "MEM_guardedalloc.h"
 
 #include "BLI_endian_defines.h"
-#include "BLI_endian_switch.h"
 #include "BLI_fileops.h"
 #include "BLI_string.h"
 #include "BLI_utildefines.h"
@@ -78,7 +77,6 @@ struct CDataFile {
 
   FILE *readf;
   FILE *writef;
-  int switchendian;
   size_t dataoffset;
 };
 
@@ -86,11 +84,8 @@ struct CDataFile {
 
 static int cdf_endian()
 {
-  if (ENDIAN_ORDER == L_ENDIAN) {
-    return CDF_ENDIAN_LITTLE;
-  }
-
-  return CDF_ENDIAN_BIG;
+  BLI_STATIC_ASSERT(ENDIAN_ORDER == L_ENDIAN, "Blender only builds on little endian systems")
+  return CDF_ENDIAN_LITTLE;
 }
 
 CDataFile *cdf_create(int type)
@@ -138,15 +133,14 @@ static bool cdf_read_header(CDataFile *cdf)
   if (header->version > CDF_VERSION) {
     return false;
   }
+  if (header->endian != cdf_endian()) {
+    return false;
+  }
 
-  cdf->switchendian = header->endian != cdf_endian();
   header->endian = cdf_endian();
 
-  if (cdf->switchendian) {
-    BLI_endian_switch_int32(&header->type);
-    BLI_endian_switch_int32(&header->totlayer);
-    BLI_endian_switch_int32(&header->structbytes);
-  }
+  /* NOTE: this is endianness-sensitive.
+   * Some non-char `header` data would need to be switched. */
 
   if (!ELEM(header->type, CDF_TYPE_IMAGE, CDF_TYPE_MESH)) {
     return false;
@@ -165,12 +159,8 @@ static bool cdf_read_header(CDataFile *cdf)
       return false;
     }
 
-    if (cdf->switchendian) {
-      BLI_endian_switch_int32(&image->width);
-      BLI_endian_switch_int32(&image->height);
-      BLI_endian_switch_int32(&image->tile_size);
-      BLI_endian_switch_int32(&image->structbytes);
-    }
+    /* NOTE: this is endianness-sensitive.
+     * Some non-char `image` data would need to be switched. */
 
     offset += image->structbytes;
     image->structbytes = sizeof(CDataFileImageHeader);
@@ -181,9 +171,8 @@ static bool cdf_read_header(CDataFile *cdf)
       return false;
     }
 
-    if (cdf->switchendian) {
-      BLI_endian_switch_int32(&mesh->structbytes);
-    }
+    /* NOTE: this is endianness-sensitive.
+     * Some non-char `mesh` data would need to be switched. */
 
     offset += mesh->structbytes;
     mesh->structbytes = sizeof(CDataFileMeshHeader);
@@ -207,12 +196,8 @@ static bool cdf_read_header(CDataFile *cdf)
       return false;
     }
 
-    if (cdf->switchendian) {
-      BLI_endian_switch_int32(&layer->type);
-      BLI_endian_switch_int32(&layer->datatype);
-      BLI_endian_switch_uint64(&layer->datasize);
-      BLI_endian_switch_int32(&layer->structbytes);
-    }
+    /* NOTE: this is endianness-sensitive.
+     * Some non-char `layer` data would need to be switched. */
 
     if (layer->datatype != CDF_DATA_FLOAT) {
       return false;
@@ -319,10 +304,8 @@ bool cdf_read_data(CDataFile *cdf, uint size, void *data)
     return false;
   }
 
-  /* switch endian if necessary */
-  if (cdf->switchendian) {
-    BLI_endian_switch_float_array(static_cast<float *>(data), size / sizeof(float));
-  }
+  /* NOTE: this is endianness-sensitive.
+   * `data` would need to be switched. */
 
   return true;
 }
diff --git a/source/blender/blenkernel/intern/idprop.cc b/source/blender/blenkernel/intern/idprop.cc
index 038d5fb84db..dd3d7709bc2 100644
--- a/source/blender/blenkernel/intern/idprop.cc
+++ b/source/blender/blenkernel/intern/idprop.cc
@@ -15,7 +15,6 @@
 
 #include <fmt/format.h>
 
-#include "BLI_endian_switch.h"
 #include "BLI_listbase.h"
 #include "BLI_math_base.h"
 #include "BLI_set.hh"
@@ -1621,18 +1620,12 @@ static void IDP_DirectLinkProperty(IDProperty *prop, BlendDataReader *reader)
       IDP_DirectLinkIDPArray(prop, reader);
       break;
     case IDP_DOUBLE:
-      /* Workaround for doubles.
-       * They are stored in the same field as `int val, val2` in the #IDPropertyData struct,
-       * they have to deal with endianness specifically.
+      /* NOTE: this is endianness-sensitive. */
+      /* Doubles are stored in the same field as `int val, val2` in the #IDPropertyData struct.
        *
-       * In theory, val and val2 would've already been swapped
-       * if switch_endian is true, so we have to first un-swap
-       * them then re-swap them as a single 64-bit entity. */
-      if (BLO_read_requires_endian_switch(reader)) {
-        BLI_endian_switch_int32(&prop->data.val);
-        BLI_endian_switch_int32(&prop->data.val2);
-        BLI_endian_switch_int64((int64_t *)&prop->data.val);
-      }
+       * In case of endianness switching, `val` and `val2` would have already been switched by the
+       * generic reading code, so they would need to be first un-switched individually, and then
+       * re-switched as a single 64-bit entity. */
       break;
     case IDP_INT:
     case IDP_FLOAT:
diff --git a/source/blender/blenkernel/intern/ipo.cc b/source/blender/blenkernel/intern/ipo.cc
index 1bf1f588b7a..7f19eea2c16 100644
--- a/source/blender/blenkernel/intern/ipo.cc
+++ b/source/blender/blenkernel/intern/ipo.cc
@@ -37,7 +37,6 @@
 #include "DNA_world_types.h"
 
 #include "BLI_dynstr.h"
-#include "BLI_endian_switch.h"
 #include "BLI_listbase.h"
 #include "BLI_string.h"
 #include "BLI_string_utils.hh"
@@ -126,38 +125,15 @@ static void ipo_blend_read_data(BlendDataReader *reader, ID *id)
 
   BLO_read_struct_list(reader, IpoCurve, &(ipo->curve));
 
+  /* NOTE: this is endianness-sensitive.
+   * Not clear why, but endianness switching was undone here for some data?
+   * That 'undo switching' code appeared to be heavily broken in 4.x code actually, performing
+   * switch on `ipo` data as part of the loop on `icu`'s, among other obvious mistakes. */
+
   LISTBASE_FOREACH (IpoCurve *, icu, &ipo->curve) {
     BLO_read_struct_array(reader, BezTriple, icu->totvert, &icu->bezt);
     BLO_read_struct_array(reader, BPoint, icu->totvert, &icu->bp);
     BLO_read_struct(reader, IpoDriver, &icu->driver);
-
-    /* Undo generic endian switching. */
-    if (BLO_read_requires_endian_switch(reader)) {
-      BLI_endian_switch_int16(&icu->blocktype);
-      if (icu->driver != nullptr) {
-
-        /* Undo generic endian switching. */
-        if (BLO_read_requires_endian_switch(reader)) {
-          BLI_endian_switch_int16(&icu->blocktype);
-          if (icu->driver != nullptr) {
-            BLI_endian_switch_int16(&icu->driver->blocktype);
-          }
-        }
-      }
-
-      /* Undo generic endian switching. */
-      if (BLO_read_requires_endian_switch(reader)) {
-        BLI_endian_switch_int16(&ipo->blocktype);
-        if (icu->driver != nullptr) {
-          BLI_endian_switch_int16(&icu->driver->blocktype);
-        }
-      }
-    }
-  }
-
-  /* Undo generic endian switching. */
-  if (BLO_read_requires_endian_switch(reader)) {
-    BLI_endian_switch_int16(&ipo->blocktype);
   }
 }
 
diff --git a/source/blender/blenkernel/intern/key.cc b/source/blender/blenkernel/intern/key.cc
index f8c2bba7178..36e24f486b5 100644
--- a/source/blender/blenkernel/intern/key.cc
+++ b/source/blender/blenkernel/intern/key.cc
@@ -14,7 +14,6 @@
 
 #include "MEM_guardedalloc.h"
 
-#include "BLI_endian_switch.h"
 #include "BLI_listbase.h"
 #include "BLI_math_matrix.h"
 #include "BLI_math_vector.h"
@@ -151,33 +150,6 @@ static void shapekey_blend_write(BlendWriter *writer, ID *id, const void *id_add
 #define IPO_BEZTRIPLE 100
 #define IPO_BPOINT 101
 
-static void switch_endian_keyblock(Key *key, KeyBlock *kb)
-{
-  int elemsize = key->elemsize;
-  char *data = static_cast<char *>(kb->data);
-
-  for (int a = 0; a < kb->totelem; a++) {
-    const char *cp = key->elemstr;
-    char *poin = data;
-
-    while (cp[0]) {    /* cp[0] == amount */
-      switch (cp[1]) { /* cp[1] = type */
-        case IPO_FLOAT:
-        case IPO_BPOINT:
-        case IPO_BEZTRIPLE: {
-          int b = cp[0];
-          BLI_endian_switch_float_array((float *)poin, b);
-          poin += sizeof(float) * b;
-          break;
-        }
-      }
-
-      cp += 2;
-    }
-    data += elemsize;
-  }
-}
-
 static void shapekey_blend_read_data(BlendDataReader *reader, ID *id)
 {
   Key *key = (Key *)id;
@@ -188,9 +160,9 @@ static void shapekey_blend_read_data(BlendDataReader *reader, ID *id)
   LISTBASE_FOREACH (KeyBlock *, kb, &key->block) {
     BLO_read_data_address(reader, &kb->data);
 
-    if (BLO_read_requires_endian_switch(reader)) {
-      switch_endian_keyblock(key, kb);
-    }
+    /* NOTE: this is endianness-sensitive. */
+    /* Keyblock data would need specific endian switching depending of the exact type of data it
+     * contain. */
   }
 }
 
diff --git a/source/blender/blenkernel/intern/mesh.cc b/source/blender/blenkernel/intern/mesh.cc
index 8722af14183..113305a3b18 100644
--- a/source/blender/blenkernel/intern/mesh.cc
+++ b/source/blender/blenkernel/intern/mesh.cc
@@ -21,7 +21,6 @@
 #include "DNA_object_types.h"
 
 #include "BLI_bounds.hh"
-#include "BLI_endian_switch.h"
 #include "BLI_hash.h"
 #include "BLI_implicit_sharing.hh"
 #include "BLI_index_range.hh"
@@ -430,12 +429,9 @@ static void mesh_blend_read_data(BlendDataReader *reader, ID *id)
     mesh->totselect = 0;
   }
 
-  if (BLO_read_requires_endian_switch(reader) && mesh->tface) {
-    TFace *tf = mesh->tface;
-    for (int i = 0; i < mesh->totface_legacy; i++, tf++) {
-      BLI_endian_switch_uint32_array(tf->col, 4);
-    }
-  }
+  /* NOTE: this is endianness-sensitive. */
+  /* Each legacy TFace would need to undo the automatic DNA switch of its array of four uint32_t
+   * RGBA colors. */
 }
 
 IDTypeInfo IDType_ID_ME = {
diff --git a/source/blender/blenkernel/intern/packedFile.cc b/source/blender/blenkernel/intern/packedFile.cc
index 0a81572f652..beb784c60bb 100644
--- a/source/blender/blenkernel/intern/packedFile.cc
+++ b/source/blender/blenkernel/intern/packedFile.cc
@@ -987,6 +987,7 @@ void BKE_packedfile_blend_read(BlendDataReader *reader, PackedFile **pf_p, Strin
   if (pf == nullptr) {
     return;
   }
+  /* NOTE: this is endianness-sensitive. */
   /* NOTE: there is no way to handle endianness switch here. */
   pf->sharing_info = BLO_read_shared(reader, &pf->data, [&]() {
     BLO_read_data_address(reader, &pf->data);
diff --git a/source/blender/blenlib/intern/BLI_mempool.cc b/source/blender/blenlib/intern/BLI_mempool.cc
index 89c3aa76064..8ef700ccc3f 100644
--- a/source/blender/blenlib/intern/BLI_mempool.cc
+++ b/source/blender/blenlib/intern/BLI_mempool.cc
@@ -46,19 +46,11 @@
 #endif
 
 /* NOTE: copied from BLO_core_bhead.hh, don't use here because we're in BLI. */
-#ifdef __BIG_ENDIAN__
-/* Big Endian */
-#  define MAKE_ID(a, b, c, d) ((int)(a) << 24 | (int)(b) << 16 | (c) << 8 | (d))
-#  define MAKE_ID_8(a, b, c, d, e, f, g, h) \
-    ((int64_t)(a) << 56 | (int64_t)(b) << 48 | (int64_t)(c) << 40 | (int64_t)(d) << 32 | \
-     (int64_t)(e) << 24 | (int64_t)(f) << 16 | (int64_t)(g) << 8 | (h))
-#else
-/* Little Endian */
-#  define MAKE_ID(a, b, c, d) (int(d) << 24 | int(c) << 16 | (b) << 8 | (a))
-#  define MAKE_ID_8(a, b, c, d, e, f, g, h) \
-    (int64_t(h) << 56 | int64_t(g) << 48 | int64_t(f) << 40 | int64_t(e) << 32 | \
-     int64_t(d) << 24 | int64_t(c) << 16 | int64_t(b) << 8 | (a))
-#endif
+/* NOTE: this is endianness-sensitive. */
+#define MAKE_ID(a, b, c, d) (int(d) << 24 | int(c) << 16 | (b) << 8 | (a))
+#define MAKE_ID_8(a, b, c, d, e, f, g, h) \
+  (int64_t(h) << 56 | int64_t(g) << 48 | int64_t(f) << 40 | int64_t(e) << 32 | int64_t(d) << 24 | \
+   int64_t(c) << 16 | int64_t(b) << 8 | (a))
 
 /**
  * Important that this value is an is _not_  aligned with `sizeof(void *)`.
diff --git a/source/blender/blenlib/intern/filereader_zstd.cc b/source/blender/blenlib/intern/filereader_zstd.cc
index 44544fa1a9b..5f16b55d4a6 100644
--- a/source/blender/blenlib/intern/filereader_zstd.cc
+++ b/source/blender/blenlib/intern/filereader_zstd.cc
@@ -13,10 +13,6 @@
 #include "BLI_fileops.hh"
 #include "BLI_filereader.h"
 
-#ifdef __BIG_ENDIAN__
-#  include "BLI_endian_switch.h"
-#endif
-
 #include "MEM_guardedalloc.h"
 
 struct ZstdReader {
@@ -43,9 +39,8 @@ static bool zstd_read_u32(FileReader *base, uint32_t *val)
   if (base->read(base, val, sizeof(uint32_t)) != sizeof(uint32_t)) {
     return false;
   }
-#ifdef __BIG_ENDIAN__
-  BLI_endian_switch_uint32(val);
-#endif
+  /* NOTE: this is endianness-sensitive.
+   * `val` would need to be switched on a big endian system. */
   return true;
 }
 
diff --git a/source/blender/blenlib/intern/hash_md5.cc b/source/blender/blenlib/intern/hash_md5.cc
index 4903da67a8c..2f902662701 100644
--- a/source/blender/blenlib/intern/hash_md5.cc
+++ b/source/blender/blenlib/intern/hash_md5.cc
@@ -70,11 +70,8 @@ struct md5_ctx {
   md5_uint32 D;
 };
 
-#ifdef __BIG_ENDIAN__
-#  define SWAP(n) (((n) << 24) | (((n) & 0xff00) << 8) | (((n) >> 8) & 0xff00) | ((n) >> 24))
-#else
-#  define SWAP(n) (n)
-#endif
+/* NOTE: this is endianness-sensitive. */
+#define SWAP(n) (n)
 
 /* This array contains the bytes used to pad the buffer to the next 64-byte boundary.
  * (RFC 1321, 3.1: Step 1) */
diff --git a/source/blender/blenlib/intern/math_color.cc b/source/blender/blenlib/intern/math_color.cc
index 43a69419b63..ac7a1a6b87f 100644
--- a/source/blender/blenlib/intern/math_color.cc
+++ b/source/blender/blenlib/intern/math_color.cc
@@ -721,11 +721,8 @@ static ushort hipart(const float f)
 
   tmp.f = f;
 
-#ifdef __BIG_ENDIAN__
-  return tmp.us[0];
-#else
+  /* NOTE: this is endianness-sensitive. */
   return tmp.us[1];
-#endif
 }
 
 static float index_to_float(const ushort i)
@@ -748,13 +745,9 @@ static float index_to_float(const ushort i)
     return -FLT_MAX;
   }
 
-#ifdef __BIG_ENDIAN__
-  tmp.us[0] = i;
-  tmp.us[1] = 0x8000;
-#else
+  /* NOTE: this is endianness-sensitive. */
   tmp.us[0] = 0x8000;
   tmp.us[1] = i;
-#endif
 
   return tmp.f;
 }
diff --git a/source/blender/blenlib/intern/math_color_inline.cc b/source/blender/blenlib/intern/math_color_inline.cc
index 396c03f8469..f63dd9889e6 100644
--- a/source/blender/blenlib/intern/math_color_inline.cc
+++ b/source/blender/blenlib/intern/math_color_inline.cc
@@ -108,11 +108,8 @@ MINLINE unsigned short to_srgb_table_lookup(const float f)
     unsigned short us[2];
   } tmp;
   tmp.f = f;
-#  ifdef __BIG_ENDIAN__
-  return BLI_color_to_srgb_table[tmp.us[0]];
-#  else
+  /* NOTE: this is endianness-sensitive. */
   return BLI_color_to_srgb_table[tmp.us[1]];
-#  endif
 }
 
 MINLINE void linearrgb_to_srgb_ushort4(unsigned short srgb[4], const float linear[4])
diff --git a/source/blender/blenlib/intern/rand.cc b/source/blender/blenlib/intern/rand.cc
index 65355ca091f..b5cf2b13c29 100644
--- a/source/blender/blenlib/intern/rand.cc
+++ b/source/blender/blenlib/intern/rand.cc
@@ -391,12 +391,9 @@ void RandomNumberGenerator::get_bytes(MutableSpan<char> r_bytes)
   int64_t i = 0;
   while (i != trim_len) {
     BLI_assert(i < trim_len);
-#ifdef __BIG_ENDIAN__
-    for (int64_t j = (rand_stride + mask_bytes) - 1; j != mask_bytes - 1; j--)
-#else
-    for (int64_t j = 0; j != rand_stride; j++)
-#endif
-    {
+    /* NOTE: this is endianness-sensitive.
+     * Big Endian needs to iterate in reverse, with a `mask_bytes - 1` offset. */
+    for (int64_t j = 0; j != rand_stride; j++) {
       r_bytes[i++] = data_src[j];
     }
     this->step();
diff --git a/source/blender/blenlib/tests/BLI_build_config_test.cc b/source/blender/blenlib/tests/BLI_build_config_test.cc
index 2594967b473..5c13ad2fdec 100644
--- a/source/blender/blenlib/tests/BLI_build_config_test.cc
+++ b/source/blender/blenlib/tests/BLI_build_config_test.cc
@@ -26,6 +26,8 @@ TEST(BLI_build_config, Endian)
 #if defined(__BIG_ENDIAN__)
   static_assert(ARCH_CPU_BIG_ENDIAN);
   static_assert(!ARCH_CPU_LITTLE_ENDIAN);
+  /* Blender does not build on big endian systems. */
+  static_assert(0);
 #endif
 #if defined(__LITTLE_ENDIAN__)
   static_assert(!ARCH_CPU_BIG_ENDIAN);
diff --git a/source/blender/blenlib/tests/BLI_hash_mm2a_test.cc b/source/blender/blenlib/tests/BLI_hash_mm2a_test.cc
index 9c8364a6cc4..2623373110c 100644
--- a/source/blender/blenlib/tests/BLI_hash_mm2a_test.cc
+++ b/source/blender/blenlib/tests/BLI_hash_mm2a_test.cc
@@ -19,11 +19,9 @@ TEST(hash_mm2a, MM2ABasic)
 
   BLI_hash_mm2a_init(&mm2, 0);
   BLI_hash_mm2a_add(&mm2, (const uchar *)data, strlen(data));
-#ifdef __LITTLE_ENDIAN__
+  /* NOTE: this is endianness-sensitive. */
+  /* On BE systems, the expected value would be 959283772. */
   EXPECT_EQ(BLI_hash_mm2a_end(&mm2), 1633988145);
-#else
-  EXPECT_EQ(BLI_hash_mm2a_end(&mm2), 959283772);
-#endif
 }
 
 TEST(hash_mm2a, MM2AConcatenateStrings)
@@ -43,11 +41,9 @@ TEST(hash_mm2a, MM2AConcatenateStrings)
   hash = BLI_hash_mm2a_end(&mm2);
   BLI_hash_mm2a_init(&mm2, 0);
   BLI_hash_mm2a_add(&mm2, (const uchar *)data123, strlen(data123));
-#ifdef __LITTLE_ENDIAN__
+  /* NOTE: this is endianness-sensitive. */
+  /* On BE systems, the expected value would be 2604964730. */
   EXPECT_EQ(hash, 1545105348);
-#else
-  EXPECT_EQ(hash, 2604964730);
-#endif
   EXPECT_EQ(BLI_hash_mm2a_end(&mm2), hash);
 }
 
@@ -66,11 +62,8 @@ TEST(hash_mm2a, MM2AIntegers)
   hash = BLI_hash_mm2a_end(&mm2);
   BLI_hash_mm2a_init(&mm2, 0);
   BLI_hash_mm2a_add(&mm2, (const uchar *)ints, sizeof(ints));
-  /* Yes, same hash here on little and big endian. */
-#ifdef __LITTLE_ENDIAN__
+  /* NOTE: this is endianness-sensitive. */
+  /* Actually, same hash here on little and big endian. */
   EXPECT_EQ(hash, 405493096);
-#else
-  EXPECT_EQ(hash, 405493096);
-#endif
   EXPECT_EQ(BLI_hash_mm2a_end(&mm2), hash);
 }
diff --git a/source/blender/blenloader/BLO_read_write.hh b/source/blender/blenloader/BLO_read_write.hh
index 2dedba211dd..db4623fadd2 100644
--- a/source/blender/blenloader/BLO_read_write.hh
+++ b/source/blender/blenloader/BLO_read_write.hh
@@ -369,7 +369,6 @@ const blender::ImplicitSharingInfo *BLO_read_shared(
 }
 
 int BLO_read_fileversion_get(BlendDataReader *reader);
-bool BLO_read_requires_endian_switch(BlendDataReader *reader);
 bool BLO_read_data_is_undo(BlendDataReader *reader);
 void BLO_read_data_globmap_add(BlendDataReader *reader, void *oldaddr, void *newaddr);
 void BLO_read_glob_list(BlendDataReader *reader, ListBase *list);
diff --git a/source/blender/blenloader/intern/readfile.cc b/source/blender/blenloader/intern/readfile.cc
index cd0732c120e..7b26b692ee6 100644
--- a/source/blender/blenloader/intern/readfile.cc
+++ b/source/blender/blenloader/intern/readfile.cc
@@ -623,12 +623,11 @@ struct BlendLibReader {
 static BHeadN *get_bhead(FileData *fd)
 {
   BHeadN *new_bhead = nullptr;
-  const bool do_endian_swap = fd->flags & FD_FLAGS_SWITCH_ENDIAN;
 
   if (fd) {
     if (!fd->is_eof) {
-      std::optional<BHead> bhead_opt = BLO_readfile_read_bhead(
-          fd->file, fd->blender_header.bhead_type(), do_endian_swap);
+      std::optional<BHead> bhead_opt = BLO_readfile_read_bhead(fd->file,
+                                                               fd->blender_header.bhead_type());
       BHead *bhead = nullptr;
       if (!bhead_opt.has_value()) {
         fd->is_eof = true;
@@ -884,10 +883,9 @@ static bool read_file_dna(FileData *fd, const char **r_error_message)
       subversion = atoi(num);
     }
     else if (bhead->code == BLO_CODE_DNA1) {
-      const bool do_endian_swap = (fd->flags & FD_FLAGS_SWITCH_ENDIAN) != 0;
+      BLI_assert((fd->flags & FD_FLAGS_SWITCH_ENDIAN) == 0);
       const bool do_alias = false; /* Postpone until after #blo_do_versions_dna runs. */
-      fd->filesdna = DNA_sdna_from_data(
-          &bhead[1], bhead->len, do_endian_swap, true, do_alias, r_error_message);
+      fd->filesdna = DNA_sdna_from_data(&bhead[1], bhead->len, true, do_alias, r_error_message);
       if (fd->filesdna) {
         blo_do_versions_dna(fd->filesdna, fd->fileversion, subversion);
         /* Allow aliased lookups (must be after version patching DNA). */
@@ -1200,7 +1198,18 @@ static FileData *blo_decode_and_check(FileData *fd, ReportList *reports)
 {
   read_blender_header(fd);
 
-  if (fd->flags & FD_FLAGS_FILE_OK) {
+  if (fd->flags & FD_FLAGS_SWITCH_ENDIAN) {
+    BLI_STATIC_ASSERT(ENDIAN_ORDER == L_ENDIAN, "Blender only builds on little endian systems")
+    BKE_reportf(reports,
+                RPT_ERROR,
+                "Blend file '%s' created by a Big Endian version of Blender, support for "
+                "these files has been removed in Blender 5.0, use an older version of Blender "
+                "to open and convert it.",
+                fd->relabase);
+    blo_filedata_free(fd);
+    fd = nullptr;
+  }
+  else if (fd->flags & FD_FLAGS_FILE_OK) {
     const char *error_message = nullptr;
     if (read_file_dna(fd, &error_message) == false) {
       BKE_reportf(
@@ -1212,22 +1221,6 @@ static FileData *blo_decode_and_check(FileData *fd, ReportList *reports)
       blo_filedata_free(fd);
       fd = nullptr;
     }
-    else if (fd->flags & FD_FLAGS_SWITCH_ENDIAN) {
-      if (ENDIAN_ORDER == L_ENDIAN) {
-        if (!BKE_reports_print_test(reports, RPT_WARNING)) {
-          CLOG_WARN(
-              &LOG,
-              "Blend file '%s' created by a Big Endian version of Blender, support for these "
-              "files will be removed in Blender 5.0",
-              fd->relabase);
-        }
-        BKE_reportf(reports,
-                    RPT_WARNING,
-                    "Blend file '%s' created by a Big Endian version of Blender, support for "
-                    "these files will be removed in Blender 5.0",
-                    fd->relabase);
-      }
-    }
   }
   else if (fd->flags & FD_FLAGS_FILE_FUTURE) {
     BKE_reportf(
@@ -1784,23 +1777,6 @@ void blo_cache_storage_end(FileData *fd)
 /** \name DNA Struct Loading
  * \{ */
 
-static void switch_endian_structs(const SDNA *filesdna, BHead *bhead)
-{
-  int blocksize, nblocks;
-  char *data;
-
-  data = (char *)(bhead + 1);
-
-  blocksize = DNA_struct_size(filesdna, bhead->SDNAnr);
-
-  nblocks = bhead->nr;
-  while (nblocks--) {
-    DNA_struct_switch_endian(filesdna, bhead->SDNAnr, data);
-
-    data += blocksize;
-  }
-}
-
 /**
  * Generate the final allocation string reference for read blocks of data. If \a blockname is
  * given, use it as 'owner block' info, otherwise use the id type index to get that info.
@@ -1897,6 +1873,7 @@ static void *read_struct(FileData *fd, BHead *bh, const char *blockname, const i
      *
      * NOTE: raw data (aka #SDNA_RAW_DATA_STRUCT_INDEX #SDNAnr) is not handled here, it's up to
      * the calling code to manage this. */
+    BLI_assert((fd->flags & FD_FLAGS_SWITCH_ENDIAN) == 0);
     BLI_STATIC_ASSERT(SDNA_RAW_DATA_STRUCT_INDEX == 0, "'raw data' SDNA struct index should be 0")
     if (bh->SDNAnr > SDNA_RAW_DATA_STRUCT_INDEX && (fd->flags & FD_FLAGS_SWITCH_ENDIAN)) {
 #ifdef USE_BHEAD_READ_ON_DEMAND
@@ -1908,7 +1885,6 @@ static void *read_struct(FileData *fd, BHead *bh, const char *blockname, const i
         }
       }
 #endif
-      switch_endian_structs(fd->filesdna, bh);
     }
 
     if (fd->compflags[bh->SDNAnr] != SDNA_CMP_REMOVED) {
@@ -4764,6 +4740,8 @@ static void library_link_end(Main *mainl, FileData **fd, const int flag, ReportL
   /* FIXME This is extremely bad design, #library_link_end should probably _always_ free the file
    * data? */
   if ((*fd)->flags & FD_FLAGS_SWITCH_ENDIAN) {
+    /* Big Endian blendfiles are not supported for linking. */
+    BLI_assert_unreachable();
     blo_filedata_free(*fd);
     *fd = nullptr;
   }
@@ -5229,11 +5207,6 @@ int BLO_read_fileversion_get(BlendDataReader *reader)
   return reader->fd->fileversion;
 }
 
-bool BLO_read_requires_endian_switch(BlendDataReader *reader)
-{
-  return (reader->fd->flags & FD_FLAGS_SWITCH_ENDIAN) != 0;
-}
-
 void BLO_read_struct_list_with_size(BlendDataReader *reader,
                                     const size_t expected_elem_size,
                                     ListBase *list)
@@ -5277,40 +5250,28 @@ void BLO_read_int16_array(BlendDataReader *reader, const int64_t array_size, int
 {
   *ptr_p = reinterpret_cast<int16_t *>(
       BLO_read_struct_array_with_size(reader, *((void **)ptr_p), sizeof(int16_t) * array_size));
-
-  if (*ptr_p && BLO_read_requires_endian_switch(reader)) {
-    BLI_endian_switch_int16_array(*ptr_p, array_size);
-  }
+  BLI_assert((reader->fd->flags & FD_FLAGS_SWITCH_ENDIAN) == 0);
 }
 
 void BLO_read_int32_array(BlendDataReader *reader, const int64_t array_size, int32_t **ptr_p)
 {
   *ptr_p = reinterpret_cast<int32_t *>(
       BLO_read_struct_array_with_size(reader, *((void **)ptr_p), sizeof(int32_t) * array_size));
-
-  if (*ptr_p && BLO_read_requires_endian_switch(reader)) {
-    BLI_endian_switch_int32_array(*ptr_p, array_size);
-  }
+  BLI_assert((reader->fd->flags & FD_FLAGS_SWITCH_ENDIAN) == 0);
 }
 
 void BLO_read_uint32_array(BlendDataReader *reader, const int64_t array_size, uint32_t **ptr_p)
 {
   *ptr_p = reinterpret_cast<uint32_t *>(
       BLO_read_struct_array_with_size(reader, *((void **)ptr_p), sizeof(uint32_t) * array_size));
-
-  if (*ptr_p && BLO_read_requires_endian_switch(reader)) {
-    BLI_endian_switch_uint32_array(*ptr_p, array_size);
-  }
+  BLI_assert((reader->fd->flags & FD_FLAGS_SWITCH_ENDIAN) == 0);
 }
 
 void BLO_read_float_array(BlendDataReader *reader, const int64_t array_size, float **ptr_p)
 {
   *ptr_p = reinterpret_cast<float *>(
       BLO_read_struct_array_with_size(reader, *((void **)ptr_p), sizeof(float) * array_size));
-
-  if (*ptr_p && BLO_read_requires_endian_switch(reader)) {
-    BLI_endian_switch_float_array(*ptr_p, array_size);
-  }
+  BLI_assert((reader->fd->flags & FD_FLAGS_SWITCH_ENDIAN) == 0);
 }
 
 void BLO_read_float3_array(BlendDataReader *reader, const int64_t array_size, float **ptr_p)
@@ -5322,10 +5283,7 @@ void BLO_read_double_array(BlendDataReader *reader, const int64_t array_size, do
 {
   *ptr_p = reinterpret_cast<double *>(
       BLO_read_struct_array_with_size(reader, *((void **)ptr_p), sizeof(double) * array_size));
-
-  if (*ptr_p && BLO_read_requires_endian_switch(reader)) {
-    BLI_endian_switch_double_array(*ptr_p, array_size);
-  }
+  BLI_assert((reader->fd->flags & FD_FLAGS_SWITCH_ENDIAN) == 0);
 }
 
 void BLO_read_string(BlendDataReader *reader, char **ptr_p)
@@ -5362,9 +5320,9 @@ static void convert_pointer_array_64_to_32(BlendDataReader *reader,
                                            const uint64_t *src,
                                            uint32_t *dst)
 {
-  const bool use_endian_swap = BLO_read_requires_endian_switch(reader);
+  BLI_assert((reader->fd->flags & FD_FLAGS_SWITCH_ENDIAN) == 0);
   for (int i = 0; i < array_size; i++) {
-    dst[i] = uint32_from_uint64_ptr(src[i], use_endian_swap);
+    dst[i] = uint32_from_uint64_ptr(src[i]);
   }
 }
 
diff --git a/source/blender/blenloader/intern/writefile.cc b/source/blender/blenloader/intern/writefile.cc
index 0d45d326dcd..fc6deac2e1c 100644
--- a/source/blender/blenloader/intern/writefile.cc
+++ b/source/blender/blenloader/intern/writefile.cc
@@ -12,12 +12,13 @@
  *
  * IFF-style structure (but not IFF compatible!)
  *
- * Start file:
- * <pre>
- * `BLENDER_V100`  `12` bytes  (version 1.00 is just an example).
- *                 `V` = big endian, `v` = little endian.
- *                 `_` = 4 byte pointer, `-` = 8 byte pointer.
- * </pre>
+ * Start of the file:
+ *
+ * Historic Blendfiles (pre-Blender 5.0):
+ * `BLENDER_V100`  : Fixed 12 bytes length. See #BLEND_FILE_FORMAT_VERSION_0 for details.
+ *
+ * Current Blendfiles (Blender 5.0 and later):
+ * `BLENDER17-01v0500`: Variable bytes length. See #BLEND_FILE_FORMAT_VERSION_1 for details.
  *
  * data-blocks: (also see struct #BHead).
  * <pre>
@@ -92,7 +93,6 @@
 #include "DNA_userdef_types.h"
 
 #include "BLI_endian_defines.h"
-#include "BLI_endian_switch.h"
 #include "BLI_fileops.hh"
 #include "BLI_implicit_sharing.hh"
 #include "BLI_math_base.h"
@@ -312,9 +312,9 @@ bool ZstdWriteWrap::open(const char *filepath)
 
 void ZstdWriteWrap::write_u32_le(uint32_t val)
 {
-  if (ENDIAN_ORDER == B_ENDIAN) {
-    BLI_endian_switch_uint32(&val);
-  }
+  /* NOTE: this is endianness-sensitive.
+   * This value must always be written as little-endian. */
+  BLI_assert(ENDIAN_ORDER == L_ENDIAN);
   base_wrap.write(&val, sizeof(uint32_t));
 }
 
@@ -1380,7 +1380,7 @@ static std::string get_blend_file_header()
   }
 
   const char pointer_size_char = sizeof(void *) == 8 ? '-' : '_';
-  const char endian_char = ENDIAN_ORDER == B_ENDIAN ? 'V' : 'v';
+  const char endian_char = 'v';
 
   /* Legacy blend file header format. */
   std::stringstream ss;
diff --git a/source/blender/blenloader_core/BLO_core_bhead.hh b/source/blender/blenloader_core/BLO_core_bhead.hh
index e58dfcd618a..d06656c7de1 100644
--- a/source/blender/blenloader_core/BLO_core_bhead.hh
+++ b/source/blender/blenloader_core/BLO_core_bhead.hh
@@ -111,9 +111,7 @@ enum {
  *
  * \return The next #BHEad or #std::nullopt if the file is exhausted.
  */
-std::optional<BHead> BLO_readfile_read_bhead(FileReader *file,
-                                             BHeadType type,
-                                             bool do_endian_swap);
+std::optional<BHead> BLO_readfile_read_bhead(FileReader *file, BHeadType type);
 
 /**
  * Converts a BHead.old pointer from 64 to 32 bit. This can't work in the general case, but only
@@ -121,12 +119,11 @@ std::optional<BHead> BLO_readfile_read_bhead(FileReader *file,
  * pointers will map to the same, which will break things later on. There is no way to check for
  * that here unfortunately.
  */
-inline uint32_t uint32_from_uint64_ptr(uint64_t ptr, const bool use_endian_swap)
+inline uint32_t uint32_from_uint64_ptr(uint64_t ptr)
 {
-  if (use_endian_swap) {
-    /* Do endian switch so that the resulting pointer is not all 0. */
-    BLI_endian_switch_uint64(&ptr);
-  }
+  /* NOTE: this is endianness-sensitive. */
+  /* Switching endianess would be required to reduce the risk of two different 64bits pointers
+   * generating the same 32bits value. */
   /* Behavior has to match #cast_pointer_64_to_32. */
   ptr >>= 3;
   return uint32_t(ptr);
diff --git a/source/blender/blenloader_core/intern/blo_core_bhead.cc b/source/blender/blenloader_core/intern/blo_core_bhead.cc
index a380dc95f43..1e0a7af13e0 100644
--- a/source/blender/blenloader_core/intern/blo_core_bhead.cc
+++ b/source/blender/blenloader_core/intern/blo_core_bhead.cc
@@ -6,48 +6,6 @@
 
 #include "BLO_core_bhead.hh"
 
-static void switch_endian_bh4(BHead4 *bhead)
-{
-  /* the ID_.. codes */
-  if ((bhead->code & 0xFFFF) == 0) {
-    bhead->code >>= 16;
-  }
-
-  if (bhead->code != BLO_CODE_ENDB) {
-    BLI_endian_switch_int32(&bhead->len);
-    BLI_endian_switch_int32(&bhead->SDNAnr);
-    BLI_endian_switch_int32(&bhead->nr);
-  }
-}
-
-static void switch_endian_small_bh8(SmallBHead8 *bhead)
-{
-  /* The ID_* codes. */
-  if ((bhead->code & 0xFFFF) == 0) {
-    bhead->code >>= 16;
-  }
-
-  if (bhead->code != BLO_CODE_ENDB) {
-    BLI_endian_switch_int32(&bhead->len);
-    BLI_endian_switch_int32(&bhead->SDNAnr);
-    BLI_endian_switch_int32(&bhead->nr);
-  }
-}
-
-static void switch_endian_large_bh8(LargeBHead8 *bhead)
-{
-  /* The ID_* codes. */
-  if ((bhead->code & 0xFFFF) == 0) {
-    bhead->code >>= 16;
-  }
-
-  if (bhead->code != BLO_CODE_ENDB) {
-    BLI_endian_switch_int64(&bhead->len);
-    BLI_endian_switch_int32(&bhead->SDNAnr);
-    BLI_endian_switch_int64(&bhead->nr);
-  }
-}
-
 static BHead bhead_from_bhead4(const BHead4 &bhead4)
 {
   BHead bhead;
@@ -59,51 +17,49 @@ static BHead bhead_from_bhead4(const BHead4 &bhead4)
   return bhead;
 }
 
-static const void *old_ptr_from_uint64_ptr(const uint64_t ptr, const bool use_endian_swap)
+static const void *old_ptr_from_uint64_ptr(const uint64_t ptr)
 {
   if constexpr (sizeof(void *) == 8) {
     return reinterpret_cast<const void *>(ptr);
   }
   else {
-    return reinterpret_cast<const void *>(uintptr_t(uint32_from_uint64_ptr(ptr, use_endian_swap)));
+    return reinterpret_cast<const void *>(uintptr_t(uint32_from_uint64_ptr(ptr)));
   }
 }
 
-static BHead bhead_from_small_bhead8(const SmallBHead8 &small_bhead8, const bool use_endian_swap)
+static BHead bhead_from_small_bhead8(const SmallBHead8 &small_bhead8)
 {
   BHead bhead;
   bhead.code = small_bhead8.code;
   bhead.len = small_bhead8.len;
-  bhead.old = old_ptr_from_uint64_ptr(small_bhead8.old, use_endian_swap);
+  bhead.old = old_ptr_from_uint64_ptr(small_bhead8.old);
   bhead.SDNAnr = small_bhead8.SDNAnr;
   bhead.nr = small_bhead8.nr;
   return bhead;
 }
 
-static BHead bhead_from_large_bhead8(const LargeBHead8 &large_bhead8, const bool use_endian_swap)
+static BHead bhead_from_large_bhead8(const LargeBHead8 &large_bhead8)
 {
   BHead bhead;
   bhead.code = large_bhead8.code;
   bhead.len = large_bhead8.len;
-  bhead.old = old_ptr_from_uint64_ptr(large_bhead8.old, use_endian_swap);
+  bhead.old = old_ptr_from_uint64_ptr(large_bhead8.old);
   bhead.SDNAnr = large_bhead8.SDNAnr;
   bhead.nr = large_bhead8.nr;
   return bhead;
 }
 
-std::optional<BHead> BLO_readfile_read_bhead(FileReader *file,
-                                             const BHeadType type,
-                                             const bool do_endian_swap)
+std::optional<BHead> BLO_readfile_read_bhead(FileReader *file, const BHeadType type)
 {
+  /* NOTE: this is endianness-sensitive. */
+  /* The various BHead data below would need to be switched if the read blend-file was saved from a
+   * system using a different endianness. */
   switch (type) {
     case BHeadType::BHead4: {
       BHead4 bhead4{};
       bhead4.code = BLO_CODE_DATA;
       const int64_t readsize = file->read(file, &bhead4, sizeof(bhead4));
       if (readsize == sizeof(bhead4) || bhead4.code == BLO_CODE_ENDB) {
-        if (do_endian_swap) {
-          switch_endian_bh4(&bhead4);
-        }
         return bhead_from_bhead4(bhead4);
       }
       break;
@@ -113,10 +69,7 @@ std::optional<BHead> BLO_readfile_read_bhead(FileReader *file,
       small_bhead8.code = BLO_CODE_DATA;
       const int64_t readsize = file->read(file, &small_bhead8, sizeof(small_bhead8));
       if (readsize == sizeof(small_bhead8) || small_bhead8.code == BLO_CODE_ENDB) {
-        if (do_endian_swap) {
-          switch_endian_small_bh8(&small_bhead8);
-        }
-        return bhead_from_small_bhead8(small_bhead8, do_endian_swap);
+        return bhead_from_small_bhead8(small_bhead8);
       }
       break;
     }
@@ -125,10 +78,7 @@ std::optional<BHead> BLO_readfile_read_bhead(FileReader *file,
       large_bhead8.code = BLO_CODE_DATA;
       const int64_t readsize = file->read(file, &large_bhead8, sizeof(large_bhead8));
       if (readsize == sizeof(large_bhead8) || large_bhead8.code == BLO_CODE_ENDB) {
-        if (do_endian_swap) {
-          switch_endian_large_bh8(&large_bhead8);
-        }
-        return bhead_from_large_bhead8(large_bhead8, do_endian_swap);
+        return bhead_from_large_bhead8(large_bhead8);
       }
       break;
     }
diff --git a/source/blender/draw/engines/eevee/eevee_precompute.hh b/source/blender/draw/engines/eevee/eevee_precompute.hh
index 8eb09631164..5d6e6a4a521 100644
--- a/source/blender/draw/engines/eevee/eevee_precompute.hh
+++ b/source/blender/draw/engines/eevee/eevee_precompute.hh
@@ -63,11 +63,9 @@ class Precompute {
     file.open(std::string(name) + ".pfm");
     file << "PF\n";
     file << n_x * n_z << " " << n_y * n_w << "\n";
-#ifdef __LITTLE_ENDIAN__
+    /* NOTE: this is endianness-sensitive.
+     * Big endian system would have needed `1.0` value instead. */
     file << "-1.0\n";
-#else
-    file << "1.0\n";
-#endif
     file.close();
 
     /* Write binary float content. */
diff --git a/source/blender/editors/armature/armature_select.cc b/source/blender/editors/armature/armature_select.cc
index c97f3fe17ef..6297ec6c0b0 100644
--- a/source/blender/editors/armature/armature_select.cc
+++ b/source/blender/editors/armature/armature_select.cc
@@ -740,13 +740,10 @@ cache_end:
         union {
           uint32_t as_u32;
           struct {
-#ifdef __BIG_ENDIAN__
-            uint16_t ob;
-            uint16_t bone;
-#else
+            /* NOTE: this is endianness-sensitive.
+             * In Big Endian the order of these two variable would have to be inverted. */
             uint16_t bone;
             uint16_t ob;
-#endif
           };
         } offset, test, best;
       } cycle_order;
diff --git a/source/blender/editors/space_view3d/view3d_select.cc b/source/blender/editors/space_view3d/view3d_select.cc
index 1f5e344d1c4..7ed019d0bca 100644
--- a/source/blender/editors/space_view3d/view3d_select.cc
+++ b/source/blender/editors/space_view3d/view3d_select.cc
@@ -38,10 +38,6 @@
 
 #include "BLT_translation.hh"
 
-#ifdef __BIG_ENDIAN__
-#  include "BLI_endian_switch.h"
-#endif
-
 #include "BKE_action.hh"
 #include "BKE_armature.hh"
 #include "BKE_attribute.hh"
@@ -2238,14 +2234,11 @@ static int gpu_select_buffer_depth_id_cmp(const void *sel_a_p, const void *sel_b
   }
 
   /* Depths match, sort by id. */
+  /* NOTE: this is endianness-sensitive.
+   * GPUSelectResult values are always expected to be little-endian. */
   uint sel_a = a->id;
   uint sel_b = b->id;
 
-#ifdef __BIG_ENDIAN__
-  BLI_endian_switch_uint32(&sel_a);
-  BLI_endian_switch_uint32(&sel_b);
-#endif
-
   if (sel_a < sel_b) {
     return -1;
   }
@@ -4225,14 +4218,11 @@ static bool do_armature_box_select(const ViewContext *vc, const rcti *rect, cons
  */
 static int gpu_bone_select_buffer_cmp(const void *sel_a_p, const void *sel_b_p)
 {
+  /* NOTE: this is endianness-sensitive.
+   * GPUSelectResult values are always expected to be little-endian. */
   uint sel_a = ((GPUSelectResult *)sel_a_p)->id;
   uint sel_b = ((GPUSelectResult *)sel_b_p)->id;
 
-#ifdef __BIG_ENDIAN__
-  BLI_endian_switch_uint32(&sel_a);
-  BLI_endian_switch_uint32(&sel_b);
-#endif
-
   if (sel_a < sel_b) {
     return -1;
   }
diff --git a/source/blender/imbuf/intern/format_dds.cc b/source/blender/imbuf/intern/format_dds.cc
index 37e3fc0b75e..3d1a9e6241d 100644
--- a/source/blender/imbuf/intern/format_dds.cc
+++ b/source/blender/imbuf/intern/format_dds.cc
@@ -21,10 +21,6 @@
 #include "BLI_path_utils.hh"
 #include "BLI_string.h"
 
-#ifdef __BIG_ENDIAN__
-#  include "BLI_endian_switch.h"
-#endif
-
 OIIO_NAMESPACE_USING
 using namespace blender::imbuf;
 
@@ -307,13 +303,11 @@ static void LoadDXTCImage(ImBuf *ibuf, Filesystem::IOMemReader &mem_reader)
    * we've made it this far. */
   uint32_t flags = 0;
   mem_reader.pread(&flags, sizeof(uint32_t), 8);
+  /* NOTE: this is endianness-sensitive. */
+  /* `ibuf->dds_data.nummipmaps` is always expected to be little-endian. */
   mem_reader.pread(&ibuf->dds_data.nummipmaps, sizeof(uint32_t), 28);
   mem_reader.pread(&ibuf->dds_data.fourcc, sizeof(uint32_t), 84);
 
-#ifdef __BIG_ENDIAN__
-  BLI_endian_switch_uint32(&ibuf->dds_data.nummipmaps);
-#endif
-
   const uint32_t DDSD_MIPMAPCOUNT = 0x00020000U;
   if ((flags & DDSD_MIPMAPCOUNT) == 0) {
     ibuf->dds_data.nummipmaps = 1;
diff --git a/source/blender/imbuf/movie/intern/movie_proxy_indexer.cc b/source/blender/imbuf/movie/intern/movie_proxy_indexer.cc
index e456d90cd24..142abca3de4 100644
--- a/source/blender/imbuf/movie/intern/movie_proxy_indexer.cc
+++ b/source/blender/imbuf/movie/intern/movie_proxy_indexer.cc
@@ -83,7 +83,9 @@ static MovieIndexBuilder *index_builder_create(const char *filepath)
   fprintf(rv->fp,
           "%s%c%.3d",
           binary_header_str,
-          (ENDIAN_ORDER == B_ENDIAN) ? 'V' : 'v',
+          /* NOTE: this is endianness-sensitive.
+           * On Big Endian system 'V' must be used instead of 'v'. */
+          'v',
           INDEX_FILE_VERSION);
 
   return rv;
@@ -179,7 +181,10 @@ static MovieIndex *movie_index_open(const char *filepath)
     return nullptr;
   }
 
-  if ((ENDIAN_ORDER == B_ENDIAN) != (header[8] == 'V')) {
+  /* NOTE: this is endianness-sensitive. */
+  BLI_assert(ELEM(header[8], 'v', 'V'));
+  const int16_t file_endianness = (header[8] == 'v') ? L_ENDIAN : B_ENDIAN;
+  if (file_endianness == B_ENDIAN) {
     for (int64_t i = 0; i < num_entries; i++) {
       BLI_endian_switch_int32(&idx->entries[i].frameno);
       BLI_endian_switch_uint64(&idx->entries[i].seek_pos_pts);
diff --git a/source/blender/imbuf/movie/intern/movie_write.cc b/source/blender/imbuf/movie/intern/movie_write.cc
index 7ff6c883bf2..309f8e4bc27 100644
--- a/source/blender/imbuf/movie/intern/movie_write.cc
+++ b/source/blender/imbuf/movie/intern/movie_write.cc
@@ -21,7 +21,6 @@
 
 #  include "MEM_guardedalloc.h"
 
-#  include "BLI_endian_defines.h"
 #  include "BLI_fileops.h"
 #  include "BLI_math_base.h"
 #  include "BLI_path_utils.hh"
@@ -254,30 +253,15 @@ static AVFrame *generate_video_frame(MovieWriter *context, const ImBuf *image)
     }
   }
   else {
-    /* Byte image: flip the image vertically, possibly with endian
-     * conversion. */
+    /* Byte image: flip the image vertically. */
     const size_t linesize_src = rgb_frame->width * 4;
     for (int y = 0; y < height; y++) {
       uint8_t *target = rgb_frame->data[0] + linesize_dst * (height - y - 1);
       const uint8_t *src = pixels + linesize_src * y;
 
-#  if ENDIAN_ORDER == L_ENDIAN
+      /* NOTE: this is endianness-sensitive. */
+      /* The target buffer is always expected to conaint little-endian RGBA values. */
       memcpy(target, src, linesize_src);
-
-#  elif ENDIAN_ORDER == B_ENDIAN
-      const uint8_t *end = src + linesize_src;
-      while (src != end) {
-        target[3] = src[0];
-        target[2] = src[1];
-        target[1] = src[2];
-        target[0] = src[3];
-
-        target += 4;
-        src += 4;
-      }
-#  else
-#    error ENDIAN_ORDER should either be L_ENDIAN or B_ENDIAN.
-#  endif
     }
   }
 
diff --git a/source/blender/makesdna/DNA_ID_enums.h b/source/blender/makesdna/DNA_ID_enums.h
index 52ccbdfe17f..e94684fee1a 100644
--- a/source/blender/makesdna/DNA_ID_enums.h
+++ b/source/blender/makesdna/DNA_ID_enums.h
@@ -97,14 +97,8 @@ typedef enum eIDPropertyFlag {
  * The tags represent types! This is a dirty way of enabling RTTI. The
  * sig_byte end endian defines aren't really used much.
  */
-
-#ifdef __BIG_ENDIAN__
-/* big endian */
-#  define MAKE_ID2(c, d) ((c) << 8 | (d))
-#else
-/* little endian */
-#  define MAKE_ID2(c, d) ((d) << 8 | (c))
-#endif
+/* NOTE: this is endianness-sensitive. */
+#define MAKE_ID2(c, d) ((d) << 8 | (c))
 
 /**
  * ID from database.
diff --git a/source/blender/makesdna/DNA_genfile.h b/source/blender/makesdna/DNA_genfile.h
index aaee664a2ec..85da301354c 100644
--- a/source/blender/makesdna/DNA_genfile.h
+++ b/source/blender/makesdna/DNA_genfile.h
@@ -24,10 +24,11 @@ extern const int DNAlen;
 
 /**
  * Primitive (non-struct, non-pointer/function/array) types,
+ *
+ * NOTE: this is endianness-sensitive.
  * \warning Don't change these values!
- * Currently changes here will work on native endianness,
- * however #DNA_struct_switch_endian currently checks these
- * hard-coded values against those from old files.
+ * Currently changes here will work on native endianness, however before 5.0,
+ * #DNA_struct_switch_endian used to check these hard-coded values against those from old files.
  */
 typedef enum eSDNA_Type {
   SDNA_TYPE_CHAR = 0,
@@ -61,8 +62,7 @@ enum eSDNA_StructCompare {
   /* Struct has disappeared
    * (values of this struct type will not be loaded by the current Blender) */
   SDNA_CMP_REMOVED = 0,
-  /* Struct is the same
-   * (can be loaded with straight memory copy after any necessary endian conversion) */
+  /* Struct is the same (can be loaded with straight memory copy). */
   SDNA_CMP_EQUAL = 1,
   /* Struct is different in some way
    * (needs to be copied/converted field by field) */
@@ -74,12 +74,8 @@ enum eSDNA_StructCompare {
 /**
  * Constructs and returns a decoded SDNA structure from the given encoded SDNA data block.
  */
-struct SDNA *DNA_sdna_from_data(const void *data,
-                                int data_len,
-                                bool do_endian_swap,
-                                bool data_alloc,
-                                bool do_alias,
-                                const char **r_error_message);
+struct SDNA *DNA_sdna_from_data(
+    const void *data, int data_len, bool data_alloc, bool do_alias, const char **r_error_message);
 void DNA_sdna_free(struct SDNA *sdna);
 
 /* Access for current Blender versions SDNA. */
@@ -137,14 +133,6 @@ bool DNA_struct_member_exists_without_alias(const struct SDNA *sdna,
                                             const char *vartype,
                                             const char *name);
 
-/**
- * Does endian swapping on the fields of a struct value.
- *
- * \param sdna: SDNA of the struct_nr belongs to
- * \param struct_nr: Index of struct info within sdna
- * \param data: Struct data that is to be converted
- */
-void DNA_struct_switch_endian(const struct SDNA *sdna, int struct_index, char *data);
 /**
  * Constructs and returns an array of byte flags with one element for each struct in oldsdna,
  * indicating how it compares to newsdna.
diff --git a/source/blender/makesdna/intern/CMakeLists.txt b/source/blender/makesdna/intern/CMakeLists.txt
index ba77fed35ed..b086689817a 100644
--- a/source/blender/makesdna/intern/CMakeLists.txt
+++ b/source/blender/makesdna/intern/CMakeLists.txt
@@ -53,7 +53,6 @@ set(BLENLIB_SRC
   ../../blenlib/intern/BLI_linklist.cc
   ../../blenlib/intern/BLI_memarena.cc
   ../../blenlib/intern/BLI_mempool.cc
-  ../../blenlib/intern/endian_switch.cc
   ../../blenlib/intern/listbase.cc
   ../../blenlib/intern/string.cc
 
diff --git a/source/blender/makesdna/intern/dna_defaults.c b/source/blender/makesdna/intern/dna_defaults.c
index fe72758c5d1..553f99c4bcf 100644
--- a/source/blender/makesdna/intern/dna_defaults.c
+++ b/source/blender/makesdna/intern/dna_defaults.c
@@ -69,7 +69,6 @@
 
 #include "MEM_guardedalloc.h"
 
-#include "BLI_endian_switch.h"
 #include "BLI_math_base.h"
 #include "BLI_math_rotation.h"
 #include "BLI_utildefines.h"
diff --git a/source/blender/makesdna/intern/dna_genfile.cc b/source/blender/makesdna/intern/dna_genfile.cc
index 0bfe18e7787..d76a3c896d6 100644
--- a/source/blender/makesdna/intern/dna_genfile.cc
+++ b/source/blender/makesdna/intern/dna_genfile.cc
@@ -23,7 +23,6 @@
 
 #include "MEM_guardedalloc.h" /* for MEM_freeN MEM_mallocN MEM_callocN */
 
-#include "BLI_endian_switch.h"
 #include "BLI_ghash.h"
 #include "BLI_index_range.hh"
 #include "BLI_math_matrix_types.hh"
@@ -42,8 +41,8 @@
  * - if you want a struct not to be in DNA file: add two hash marks above it `(#<enter>#<enter>)`.
  *
  * Structure DNA data is added to each blender file and to each executable, this to detect
- * in .blend files new variables in structs, changed array sizes, etc. It's also used for
- * converting endian and pointer size (32-64 bits)
+ * in .blend files new variables in structs, changed array sizes, etc. It is also used for
+ * converting pointer size (32-64 bits) (and it used to be to handle endianness).
  * As an extra, Python uses a call to detect run-time the contents of a blender struct.
  *
  * Create a structDNA: only needed when one of the input include (.h) files change.
@@ -95,7 +94,6 @@
  *  - array (`vec[3]`) to float struct (`vec3f`).
  *
  * DONE:
- *  - Endian compatibility.
  *  - Pointer conversion (32-64 bits).
  *
  * IMPORTANT:
@@ -117,13 +115,9 @@
  *    always check blender running from a console.
  */
 
-#ifdef __BIG_ENDIAN__
-/* Big Endian */
-#  define MAKE_ID(a, b, c, d) (int(a) << 24 | int(b) << 16 | (c) << 8 | (d))
-#else
+/* NOTE: this is endianness-sensitive. */
 /* Little Endian */
-#  define MAKE_ID(a, b, c, d) (int(d) << 24 | int(c) << 16 | (b) << 8 | (a))
-#endif
+#define MAKE_ID(a, b, c, d) (int(d) << 24 | int(c) << 16 | (b) << 8 | (a))
 
 /* ************************* DIV ********************** */
 
@@ -322,7 +316,7 @@ BLI_INLINE const char *pad_up_4(const char *ptr)
 /**
  * In sdna->data the data, now we convert that to something understandable
  */
-static bool init_structDNA(SDNA *sdna, bool do_endian_swap, const char **r_error_message)
+static bool init_structDNA(SDNA *sdna, const char **r_error_message)
 {
   int member_index_gravity_fix = -1;
 
@@ -358,10 +352,8 @@ static bool init_structDNA(SDNA *sdna, bool do_endian_swap, const char **r_error
   if (*data == MAKE_ID('N', 'A', 'M', 'E')) {
     data++;
 
+    /* NOTE: this is endianness-sensitive. */
     sdna->members_num = *data;
-    if (do_endian_swap) {
-      BLI_endian_switch_int32(&sdna->members_num);
-    }
     sdna->members_num_alloc = sdna->members_num;
 
     data++;
@@ -398,10 +390,8 @@ static bool init_structDNA(SDNA *sdna, bool do_endian_swap, const char **r_error
   if (*data == MAKE_ID('T', 'Y', 'P', 'E')) {
     data++;
 
+    /* NOTE: this is endianness-sensitive. */
     sdna->types_num = *data;
-    if (do_endian_swap) {
-      BLI_endian_switch_int32(&sdna->types_num);
-    }
 
     data++;
     sdna->types = MEM_calloc_arrayN<const char *>(sdna->types_num, "sdnatypes");
@@ -428,13 +418,10 @@ static bool init_structDNA(SDNA *sdna, bool do_endian_swap, const char **r_error
   short *sp;
   if (*data == MAKE_ID('T', 'L', 'E', 'N')) {
     data++;
+    /* NOTE: this is endianness-sensitive. */
     sp = (short *)data;
     sdna->types_size = sp;
 
-    if (do_endian_swap) {
-      BLI_endian_switch_int16_array(sp, sdna->types_num);
-    }
-
     sp += sdna->types_num;
   }
   if (!sdna->types_size) {
@@ -451,10 +438,8 @@ static bool init_structDNA(SDNA *sdna, bool do_endian_swap, const char **r_error
   if (*data == MAKE_ID('S', 'T', 'R', 'C')) {
     data++;
 
+    /* NOTE: this is endianness-sensitive. */
     sdna->structs_num = *data;
-    if (do_endian_swap) {
-      BLI_endian_switch_int32(&sdna->structs_num);
-    }
 
     data++;
     sdna->structs = MEM_calloc_arrayN<SDNA_Struct *>(sdna->structs_num, "sdnastrcs");
@@ -468,19 +453,10 @@ static bool init_structDNA(SDNA *sdna, bool do_endian_swap, const char **r_error
   blender::Set<short> struct_indices;
   sp = (short *)data;
   for (int struct_index = 0; struct_index < sdna->structs_num; struct_index++) {
+    /* NOTE: this is endianness-sensitive. */
     SDNA_Struct *struct_info = (SDNA_Struct *)sp;
     sdna->structs[struct_index] = struct_info;
 
-    if (do_endian_swap) {
-      BLI_endian_switch_int16(&struct_info->type_index);
-      BLI_endian_switch_int16(&struct_info->members_num);
-
-      for (short a = 0; a < struct_info->members_num; a++) {
-        SDNA_StructMember *member = &struct_info->members[a];
-        BLI_endian_switch_int16(&member->type_index);
-        BLI_endian_switch_int16(&member->member_index);
-      }
-    }
     if (!struct_indices.add(struct_info->type_index)) {
       *r_error_message = "Invalid duplicate struct type index in SDNA file";
       return false;
@@ -572,7 +548,6 @@ static bool init_structDNA(SDNA *sdna, bool do_endian_swap, const char **r_error
 
 SDNA *DNA_sdna_from_data(const void *data,
                          const int data_len,
-                         bool do_endian_swap,
                          bool data_alloc,
                          const bool do_alias,
                          const char **r_error_message)
@@ -591,7 +566,7 @@ SDNA *DNA_sdna_from_data(const void *data,
   }
   sdna->data_alloc = data_alloc;
 
-  if (init_structDNA(sdna, do_endian_swap, &error_message)) {
+  if (init_structDNA(sdna, &error_message)) {
     if (do_alias) {
       DNA_sdna_alias_data_ensure_structs_map(sdna);
     }
@@ -618,7 +593,7 @@ static SDNA *g_sdna = nullptr;
 
 void DNA_sdna_current_init()
 {
-  g_sdna = DNA_sdna_from_data(DNAstr, DNAlen, false, false, true, nullptr);
+  g_sdna = DNA_sdna_from_data(DNAstr, DNAlen, false, true, nullptr);
 }
 
 const SDNA *DNA_sdna_current_get()
@@ -755,7 +730,8 @@ const char *DNA_struct_get_compareflags(const SDNA *oldsdna, const SDNA *newsdna
    *   - `struct Link` never needed DNA-versioning.
    *
    * NOTE: This may have been broken in BE/LE conversion cases, however this endianness handling
-   * code have likely been dead/never used in practice for many years now.
+   * code have likely been dead/never used in practice for many years, and has been removed in
+   * Blender 5.0.
    */
   BLI_STATIC_ASSERT(SDNA_RAW_DATA_STRUCT_INDEX == 0, "'raw data' SDNA struct index should be 0")
   compare_flags[SDNA_RAW_DATA_STRUCT_INDEX] = SDNA_CMP_EQUAL;
@@ -1115,74 +1091,6 @@ static int get_member_size_in_bytes(const SDNA *sdna, const SDNA_StructMember *m
   return type_size * array_length;
 }
 
-void DNA_struct_switch_endian(const SDNA *sdna, int struct_index, char *data)
-{
-  if (struct_index == -1) {
-    return;
-  }
-
-  const SDNA_Struct *struct_info = sdna->structs[struct_index];
-
-  int offset_in_bytes = 0;
-  for (int member_index = 0; member_index < struct_info->members_num; member_index++) {
-    const SDNA_StructMember *member = &struct_info->members[member_index];
-    const eStructMemberCategory member_category = get_struct_member_category(sdna, member);
-    char *member_data = data + offset_in_bytes;
-    const char *member_type_name = sdna->types[member->type_index];
-    const int member_array_length = sdna->members_array_num[member->member_index];
-
-    switch (member_category) {
-      case STRUCT_MEMBER_CATEGORY_STRUCT: {
-        const int substruct_size = sdna->types_size[member->type_index];
-        const int substruct_index = DNA_struct_find_index_without_alias(sdna, member_type_name);
-        BLI_assert(substruct_index != -1);
-        for (int a = 0; a < member_array_length; a++) {
-          DNA_struct_switch_endian(sdna, substruct_index, member_data + a * substruct_size);
-        }
-        break;
-      }
-      case STRUCT_MEMBER_CATEGORY_PRIMITIVE: {
-        switch (member->type_index) {
-          case SDNA_TYPE_SHORT:
-          case SDNA_TYPE_USHORT: {
-            BLI_endian_switch_int16_array((int16_t *)member_data, member_array_length);
-            break;
-          }
-          case SDNA_TYPE_INT:
-          case SDNA_TYPE_FLOAT: {
-            /* NOTE: intentionally ignore `long/ulong`, because these could be 4 or 8 bytes.
-             * Fortunately, we only use these types for runtime variables and only once for a
-             * struct type that is no longer used. */
-            BLI_endian_switch_int32_array((int32_t *)member_data, member_array_length);
-            break;
-          }
-          case SDNA_TYPE_INT64:
-          case SDNA_TYPE_UINT64:
-          case SDNA_TYPE_DOUBLE: {
-            BLI_endian_switch_int64_array((int64_t *)member_data, member_array_length);
-            break;
-          }
-          default: {
-            break;
-          }
-        }
-        break;
-      }
-      case STRUCT_MEMBER_CATEGORY_POINTER: {
-        /* See `readfile.cc` (#uint32_from_uint64_ptr swap endian argument),
-         * this is only done when reducing the size of a pointer from 4 to 8. */
-        if (sizeof(void *) < 8) {
-          if (sdna->pointer_size == 8) {
-            BLI_endian_switch_uint64_array((uint64_t *)member_data, member_array_length);
-          }
-        }
-        break;
-      }
-    }
-    offset_in_bytes += get_member_size_in_bytes(sdna, member);
-  }
-}
-
 enum eReconstructStepType {
   RECONSTRUCT_STEP_MEMCPY,
   RECONSTRUCT_STEP_CAST_PRIMITIVE,
diff --git a/source/blender/makesrna/intern/rna_define.cc b/source/blender/makesrna/intern/rna_define.cc
index 277f456b57d..6db4ac9315e 100644
--- a/source/blender/makesrna/intern/rna_define.cc
+++ b/source/blender/makesrna/intern/rna_define.cc
@@ -707,7 +707,7 @@ BlenderRNA *RNA_create()
   /* We need both alias and static (on-disk) DNA names. */
   const bool do_alias = true;
 
-  DefRNA.sdna = DNA_sdna_from_data(DNAstr, DNAlen, false, false, do_alias, &error_message);
+  DefRNA.sdna = DNA_sdna_from_data(DNAstr, DNAlen, false, do_alias, &error_message);
   if (DefRNA.sdna == nullptr) {
     CLOG_ERROR(&LOG, "Failed to decode SDNA: %s.", error_message);
     DefRNA.error = true;
diff --git a/source/blender/modifiers/intern/MOD_meshcache_mdd.cc b/source/blender/modifiers/intern/MOD_meshcache_mdd.cc
index 7cc26ffc700..28070b6c956 100644
--- a/source/blender/modifiers/intern/MOD_meshcache_mdd.cc
+++ b/source/blender/modifiers/intern/MOD_meshcache_mdd.cc
@@ -11,11 +11,9 @@
 #include <cstdio>
 #include <cstring>
 
+#include "BLI_endian_switch.h"
 #include "BLI_fileops.h"
 #include "BLI_math_base.h"
-#ifdef __LITTLE_ENDIAN__
-#  include "BLI_endian_switch.h"
-#endif
 #ifdef WIN32
 #  include "BLI_winstuff.h"
 #endif
@@ -41,9 +39,9 @@ static bool meshcache_read_mdd_head(FILE *fp,
     return false;
   }
 
-#ifdef __LITTLE_ENDIAN__
+  /* NOTE: this is endianness-sensitive. */
+  /* MDD is big-endian, its values need to be switched on little-endian systems. */
   BLI_endian_switch_int32_array((int *)mdd_head, 2);
-#endif
 
   if (mdd_head->verts_tot != verts_tot) {
     *r_err_str = RPT_("Vertex count mismatch");
@@ -104,9 +102,10 @@ static bool meshcache_read_mdd_range_from_time(FILE *fp,
   errno = 0;
   for (i = 0; i < mdd_head.frame_tot; i++) {
     frames_num_read += fread(&f_time, sizeof(float), 1, fp);
-#ifdef __LITTLE_ENDIAN__
+    /* NOTE: this is endianness-sensitive. */
+    /* MDD is big-endian, its values need to be switched on little-endian systems. */
     BLI_endian_switch_float(&f_time);
-#endif
+
     if (f_time >= time) {
       frames_num_expect = i + 1;
       break;
@@ -169,11 +168,11 @@ bool MOD_meshcache_read_mdd_index(FILE *fp,
     for (i = mdd_head.verts_tot; i != 0; i--, vco += 3) {
       verts_read_num += fread(vco, sizeof(float[3]), 1, fp);
 
-#  ifdef __LITTLE_ENDIAN__
+      /* NOTE: this is endianness-sensitive. */
+      /* MDD is big-endian, its values need to be switched on little-endian systems. */
       BLI_endian_switch_float(vco + 0);
       BLI_endian_switch_float(vco + 1);
       BLI_endian_switch_float(vco + 2);
-#  endif /* __LITTLE_ENDIAN__ */
     }
 #else
     /* no blending */
@@ -181,9 +180,9 @@ bool MOD_meshcache_read_mdd_index(FILE *fp,
       *r_err_str = errno ? strerror(errno) : RPT_("Failed to read frame");
       return false;
     }
-#  ifdef __LITTLE_ENDIAN__
+    /* NOTE: this is endianness-sensitive. */
+    /* MDD is big-endian, its values need to be switched on little-endian systems. */
     BLI_endian_switch_float_array(vertexCos[0], mdd_head.verts_tot * 3);
-#  endif
 #endif
   }
   else {
@@ -194,11 +193,11 @@ bool MOD_meshcache_read_mdd_index(FILE *fp,
       float tvec[3];
       verts_read_num += fread(tvec, sizeof(float[3]), 1, fp);
 
-#ifdef __LITTLE_ENDIAN__
+      /* NOTE: this is endianness-sensitive. */
+      /* MDD is big-endian, its values need to be switched on little-endian systems. */
       BLI_endian_switch_float(tvec + 0);
       BLI_endian_switch_float(tvec + 1);
       BLI_endian_switch_float(tvec + 2);
-#endif
 
       vco[0] = (vco[0] * ifactor) + (tvec[0] * factor);
       vco[1] = (vco[1] * ifactor) + (tvec[1] * factor);
diff --git a/source/blender/modifiers/intern/MOD_meshcache_pc2.cc b/source/blender/modifiers/intern/MOD_meshcache_pc2.cc
index 292fe60e3de..5ec010c311e 100644
--- a/source/blender/modifiers/intern/MOD_meshcache_pc2.cc
+++ b/source/blender/modifiers/intern/MOD_meshcache_pc2.cc
@@ -14,9 +14,6 @@
 #include "BLI_utildefines.h"
 
 #include "BLI_fileops.h"
-#ifdef __BIG_ENDIAN__
-#  include "BLI_endian_switch.h"
-#endif
 
 #ifdef WIN32
 #  include "BLI_winstuff.h"
@@ -52,10 +49,9 @@ static bool meshcache_read_pc2_head(FILE *fp,
     return false;
   }
 
-#ifdef __BIG_ENDIAN__
-  BLI_endian_switch_int32_array(&pc2_head->file_version,
-                                (sizeof(*pc2_head) - sizeof(pc2_head->header)) / sizeof(int));
-#endif
+  /* NOTE: this is endianness-sensitive. */
+  /* The pc2_head->file_version and following values would need to be switched on big-endian
+   * systems. */
 
   if (pc2_head->verts_tot != verts_tot) {
     *r_err_str = RPT_("Vertex count mismatch");
@@ -150,11 +146,8 @@ bool MOD_meshcache_read_pc2_index(FILE *fp,
     for (i = pc2_head.verts_tot; i != 0; i--, vco += 3) {
       verts_read_num += fread(vco, sizeof(float[3]), 1, fp);
 
-#ifdef __BIG_ENDIAN__
-      BLI_endian_switch_float(vco + 0);
-      BLI_endian_switch_float(vco + 1);
-      BLI_endian_switch_float(vco + 2);
-#endif /* __BIG_ENDIAN__ */
+      /* NOTE: this is endianness-sensitive. */
+      /* The `vco` values would need to be switched on big-endian systems. */
     }
   }
   else {
@@ -165,11 +158,8 @@ bool MOD_meshcache_read_pc2_index(FILE *fp,
       float tvec[3];
       verts_read_num += fread(tvec, sizeof(float[3]), 1, fp);
 
-#ifdef __BIG_ENDIAN__
-      BLI_endian_switch_float(tvec + 0);
-      BLI_endian_switch_float(tvec + 1);
-      BLI_endian_switch_float(tvec + 2);
-#endif /* __BIG_ENDIAN__ */
+      /* NOTE: this is endianness-sensitive. */
+      /* The `tvec` values would need to be switched on big-endian systems. */
 
       vco[0] = (vco[0] * ifactor) + (tvec[0] * factor);
       vco[1] = (vco[1] * ifactor) + (tvec[1] * factor);
diff --git a/source/blender/python/mathutils/mathutils_Euler.cc b/source/blender/python/mathutils/mathutils_Euler.cc
index 961681308ad..566c9ecd002 100644
--- a/source/blender/python/mathutils/mathutils_Euler.cc
+++ b/source/blender/python/mathutils/mathutils_Euler.cc
@@ -39,11 +39,8 @@ short euler_order_from_string(const char *str, const char *error_prefix)
 {
   if (str[0] && str[1] && str[2] && str[3] == '\0') {
 
-#ifdef __LITTLE_ENDIAN__
-#  define MAKE_ID3(a, b, c) ((a) | ((b) << 8) | ((c) << 16))
-#else
-#  define MAKE_ID3(a, b, c) (((a) << 24) | ((b) << 16) | ((c) << 8))
-#endif
+/* NOTE: this is endianness-sensitive. */
+#define MAKE_ID3(a, b, c) ((a) | ((b) << 8) | ((c) << 16))
 
     switch (*((const PY_INT32_T *)str)) {
       case MAKE_ID3('X', 'Y', 'Z'):
diff --git a/source/creator/creator.cc b/source/creator/creator.cc
index ec585b3e3d4..1c68b96afee 100644
--- a/source/creator/creator.cc
+++ b/source/creator/creator.cc
@@ -28,6 +28,7 @@
 
 #include "DNA_genfile.h"
 
+#include "BLI_endian_defines.h"
 #include "BLI_fftw.hh"
 #include "BLI_string.h"
 #include "BLI_system.h"
@@ -98,6 +99,8 @@
 
 #include "creator_intern.h" /* Own include. */
 
+BLI_STATIC_ASSERT(ENDIAN_ORDER == L_ENDIAN, "Blender only builds on little endian systems")
+
 /* -------------------------------------------------------------------- */
 /** \name Local Defines
  * \{ */
diff --git a/tests/python/bl_blendfile_versioning.py b/tests/python/bl_blendfile_versioning.py
index 26659b45114..aad022a3978 100644
--- a/tests/python/bl_blendfile_versioning.py
+++ b/tests/python/bl_blendfile_versioning.py
@@ -31,30 +31,205 @@ class TestBlendFileOpenAllTestFiles(TestHelper):
         # Each file in this list should either be the source of a bug report,
         # or removed from tests repo.
         self.excluded_paths = {
-            # tests/modifier_stack/explode_modifier.blend
+            # modifier_stack/explode_modifier.blend
             # BLI_assert failed: source/blender/blenlib/BLI_ordered_edge.hh:41, operator==(), at 'e1.v_low < e1.v_high'
             "explode_modifier.blend",
 
-            # tests/depsgraph/deg_anim_camera_dof_driving_material.blend
+            # depsgraph/deg_anim_camera_dof_driving_material.blend
             # ERROR (bke.fcurve):
             # source/blender/blenkernel/intern/fcurve_driver.cc:188 dtar_get_prop_val:
             # Driver Evaluation Error: cannot resolve target for OBCamera ->
             # data.dof_distance
             "deg_anim_camera_dof_driving_material.blend",
 
-            # tests/depsgraph/deg_driver_shapekey_same_datablock.blend
+            # depsgraph/deg_driver_shapekey_same_datablock.blend
             # Error: Not freed memory blocks: 4, total unfreed memory 0.000427 MB
             "deg_driver_shapekey_same_datablock.blend",
 
-            # tests/physics/fluidsim.blend
+            # physics/fluidsim.blend
             # Error: Not freed memory blocks: 3, total unfreed memory 0.003548 MB
             "fluidsim.blend",
 
-            # tests/opengl/ram_glsl.blend
+            # opengl/ram_glsl.blend
             # Error: Not freed memory blocks: 4, total unfreed memory 0.000427 MB
             "ram_glsl.blend",
         }
 
+        # Some files are expected to be invalid.
+        # This mapping stores filenames as keys, and expected error message as value.
+        self.invalid_paths = {
+            # animation/driver-object-eyes.blend
+            # File generated from a big endian build of Blender.
+            "driver-object-eyes.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+
+            # modeling/faceselectmode.blend
+            # File generated from a big endian build of Blender.
+            "faceselectmode.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # modeling/weight-paint_test.blend
+            # File generated from a big endian build of Blender.
+            "weight-paint_test.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+
+            # io_tests/blend_big_endian/1.62/glass.blend
+            # File generated from a big endian build of Blender.
+            "glass.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/1.62/room.blend
+            # File generated from a big endian build of Blender.
+            "room.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/1.69/s-mesh.blend
+            # File generated from a big endian build of Blender.
+            "s-mesh.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/1.70/escher.blend
+            # File generated from a big endian build of Blender.
+            "escher.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/1.98/egypt.blend
+            # File generated from a big endian build of Blender.
+            "egypt.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.25/FroggyPacked.blend
+            # File generated from a big endian build of Blender.
+            "FroggyPacked.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.30/CtrlObject.blend
+            # File generated from a big endian build of Blender.
+            "CtrlObject.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.30/demofile.blend
+            # File generated from a big endian build of Blender.
+            "demofile.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.30/dolphin.blend
+            # File generated from a big endian build of Blender.
+            "dolphin.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.30/mball.blend
+            # File generated from a big endian build of Blender.
+            "mball.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.30/motor9.blend
+            # File generated from a big endian build of Blender.
+            "motor9.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.30/relative.blend
+            # File generated from a big endian build of Blender.
+            "relative.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.31/Raptor.blend
+            # File generated from a big endian build of Blender.
+            "Raptor.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.31/allselect.blend
+            # File generated from a big endian build of Blender.
+            "allselect.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.31/arealight.blend
+            # File generated from a big endian build of Blender.
+            "arealight.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.31/hairball.blend
+            # File generated from a big endian build of Blender.
+            "hairball.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.31/luxo.blend
+            # File generated from a big endian build of Blender.
+            "luxo.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.31/monkey_cornelius.blend
+            # File generated from a big endian build of Blender.
+            "monkey_cornelius.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.31/refract_monkey.blend
+            # File generated from a big endian build of Blender.
+            "refract_monkey.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.31/robo.blend
+            # File generated from a big endian build of Blender.
+            "robo.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.34/flippedmatrixes.blend
+            # File generated from a big endian build of Blender.
+            "flippedmatrixes.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.34/lostride.blend
+            # File generated from a big endian build of Blender.
+            "lostride.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.34/tapercurve.blend
+            # File generated from a big endian build of Blender.
+            "tapercurve.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.36/pathdist.blend
+            # File generated from a big endian build of Blender.
+            "pathdist.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+            # io_tests/blend_big_endian/2.76/bird_sintel.blend
+            # File generated from a big endian build of Blender.
+            "bird_sintel.blend": (
+                (OSError, RuntimeError),
+                "created by a Big Endian version of Blender, support for these files has been removed in Blender 5.0"
+            ),
+        }
+
         # Directories to exclude relative to `./tests/files/`.
         self.excluded_dirs = ()
 
@@ -102,6 +277,18 @@ class TestBlendFileOpenAllTestFiles(TestHelper):
                 return True
         return False
 
+    def invalid_path_exception_process(self, bfp, exception):
+        expected_failure = self.invalid_paths.get(os.path.basename(bfp), None)
+        if not expected_failure:
+            raise exception
+        # Check expected exception type(s).
+        if not isinstance(exception, expected_failure[0]):
+            raise exception
+        # Check expected exception (partial) message.
+        if expected_failure[1] not in str(exception):
+            raise exception
+        print(f"\tExpected failure: '{exception}'", flush=True)
+
     def test_open(self):
         for bfp in self.blendfile_paths:
             if self.skip_path_check(bfp):
@@ -109,7 +296,10 @@ class TestBlendFileOpenAllTestFiles(TestHelper):
             if not self.args.is_quiet:
                 print(f"Trying to open {bfp}", flush=True)
             bpy.ops.wm.read_homefile(use_empty=True, use_factory_startup=True)
-            bpy.ops.wm.open_mainfile(filepath=bfp, load_ui=False)
+            try:
+                bpy.ops.wm.open_mainfile(filepath=bfp, load_ui=False)
+            except BaseException as e:
+                self.invalid_path_exception_process(bfp, e)
 
     def link_append(self, do_link):
         operation_name = "link" if do_link else "append"
@@ -117,15 +307,18 @@ class TestBlendFileOpenAllTestFiles(TestHelper):
             if self.skip_path_check(bfp):
                 continue
             bpy.ops.wm.read_homefile(use_empty=True, use_factory_startup=True)
-            with bpy.data.libraries.load(bfp, link=do_link) as (lib_in, lib_out):
-                if len(lib_in.collections):
-                    if not self.args.is_quiet:
-                        print(f"Trying to {operation_name} {bfp}/Collection/{lib_in.collections[0]}", flush=True)
-                    lib_out.collections.append(lib_in.collections[0])
-                elif len(lib_in.objects):
-                    if not self.args.is_quiet:
-                        print(f"Trying to {operation_name} {bfp}/Object/{lib_in.objects[0]}", flush=True)
-                    lib_out.objects.append(lib_in.objects[0])
+            try:
+                with bpy.data.libraries.load(bfp, link=do_link) as (lib_in, lib_out):
+                    if len(lib_in.collections):
+                        if not self.args.is_quiet:
+                            print(f"Trying to {operation_name} {bfp}/Collection/{lib_in.collections[0]}", flush=True)
+                        lib_out.collections.append(lib_in.collections[0])
+                    elif len(lib_in.objects):
+                        if not self.args.is_quiet:
+                            print(f"Trying to {operation_name} {bfp}/Object/{lib_in.objects[0]}", flush=True)
+                        lib_out.objects.append(lib_in.objects[0])
+            except BaseException as e:
+                self.invalid_path_exception_process(bfp, e)
 
     def test_link(self):
         self.link_append(do_link=True)