diff --git a/changelog.d/10029.bugfix b/changelog.d/10029.bugfix
new file mode 100644
index 000000000..c214cbdae
--- /dev/null
+++ b/changelog.d/10029.bugfix
@@ -0,0 +1 @@
+Fixed a bug with very high resolution image uploads throwing internal server errors.
\ No newline at end of file
diff --git a/synapse/rest/media/v1/media_repository.py b/synapse/rest/media/v1/media_repository.py
index e8a875b90..21c43c340 100644
--- a/synapse/rest/media/v1/media_repository.py
+++ b/synapse/rest/media/v1/media_repository.py
@@ -76,6 +76,8 @@ class MediaRepository:
         self.max_upload_size = hs.config.max_upload_size
         self.max_image_pixels = hs.config.max_image_pixels
 
+        Thumbnailer.set_limits(self.max_image_pixels)
+
         self.primary_base_path = hs.config.media_store_path  # type: str
         self.filepaths = MediaFilePaths(self.primary_base_path)  # type: MediaFilePaths
 
diff --git a/synapse/rest/media/v1/thumbnailer.py b/synapse/rest/media/v1/thumbnailer.py
index 37fe58239..a65e9e180 100644
--- a/synapse/rest/media/v1/thumbnailer.py
+++ b/synapse/rest/media/v1/thumbnailer.py
@@ -40,6 +40,10 @@ class Thumbnailer:
 
     FORMATS = {"image/jpeg": "JPEG", "image/png": "PNG"}
 
+    @staticmethod
+    def set_limits(max_image_pixels: int):
+        Image.MAX_IMAGE_PIXELS = max_image_pixels
+
     def __init__(self, input_path: str):
         try:
             self.image = Image.open(input_path)
@@ -47,6 +51,11 @@ class Thumbnailer:
             # If an error occurs opening the image, a thumbnail won't be able to
             # be generated.
             raise ThumbnailError from e
+        except Image.DecompressionBombError as e:
+            # If an image decompression bomb error occurs opening the image,
+            # then the image exceeds the pixel limit and a thumbnail won't
+            # be able to be generated.
+            raise ThumbnailError from e
 
         self.width, self.height = self.image.size
         self.transpose_method = None