diff --git a/changelog.d/11454.bugfix b/changelog.d/11454.bugfix
new file mode 100644
index 000000000000..096265cbc933
--- /dev/null
+++ b/changelog.d/11454.bugfix
@@ -0,0 +1 @@
+Fix an `LruCache` corruption bug, introduced in 1.38.0, that would cause certain requests to fail until the next Synapse restart.
diff --git a/synapse/util/caches/lrucache.py b/synapse/util/caches/lrucache.py
index 05c4dcb062a8..eb96f7e665e6 100644
--- a/synapse/util/caches/lrucache.py
+++ b/synapse/util/caches/lrucache.py
@@ -271,7 +271,10 @@ def drop_from_cache(self) -> None:
         removed from all lists.
         """
         cache = self._cache()
-        if not cache or not cache.pop(self.key, None):
+        if (
+            cache is None
+            or cache.pop(self.key, _Sentinel.sentinel) is _Sentinel.sentinel
+        ):
             # `cache.pop` should call `drop_from_lists()`, unless this Node had
             # already been removed from the cache.
             self.drop_from_lists()
diff --git a/tests/util/test_lrucache.py b/tests/util/test_lrucache.py
index 6578f3411e27..291644eb7dd0 100644
--- a/tests/util/test_lrucache.py
+++ b/tests/util/test_lrucache.py
@@ -13,6 +13,7 @@
 # limitations under the License.
 
 
+from typing import List
 from unittest.mock import Mock
 
 from synapse.util.caches.lrucache import LruCache, setup_expire_lru_cache_entries
@@ -261,6 +262,17 @@ def test_evict(self):
         self.assertEquals(cache["key4"], [4])
         self.assertEquals(cache["key5"], [5, 6])
 
+    def test_zero_size_drop_from_cache(self) -> None:
+        """Test that `drop_from_cache` works correctly with 0-sized entries."""
+        cache: LruCache[str, List[int]] = LruCache(5, size_callback=lambda x: 0)
+        cache["key1"] = []
+
+        self.assertEqual(len(cache), 0)
+        cache.cache["key1"].drop_from_cache()
+        self.assertIsNone(
+            cache.pop("key1"), "Cache entry should have been evicted but wasn't"
+        )
+
 
 class TimeEvictionTestCase(unittest.HomeserverTestCase):
     """Test that time based eviction works correctly."""