diff --git a/changelog.d/19690.bugfix b/changelog.d/19690.bugfix
new file mode 100644
index 0000000000..3aa0dd11f3
--- /dev/null
+++ b/changelog.d/19690.bugfix
@@ -0,0 +1 @@
+Fix database migrations failing on platforms where SQLite is configured with `SQLITE_DBCONFIG_DEFENSIVE` by default, such as macOS.
\ No newline at end of file
diff --git a/docs/development/contributing_guide.md b/docs/development/contributing_guide.md
index 7e0dd4059d..ab506b5f05 100644
--- a/docs/development/contributing_guide.md
+++ b/docs/development/contributing_guide.md
@@ -309,21 +309,6 @@ works without further arguments).
 Your Postgres account needs to be able to create databases; see the postgres
 docs for [`ALTER ROLE`](https://www.postgresql.org/docs/current/sql-alterrole.html).
 
-### Running the tests on MacOS
-
-To run the unit tests with SQLite on MacOS you will need to swap out the default MacOS
-python interpreter with the homebrew version. This is due to the default using a
-locked down version of Python and sqlite3. After installing python from homebrew:
-
-```
-  poetry env remove --all
-  poetry env use /opt/homebrew/bin/python3.13
-  poetry install
-  poetry run trial tests
-```
-
-This example uses python 3.13, but choose whichever version you want.
-
 ## Run the integration tests ([Sytest](https://github.com/matrix-org/sytest)).
 
 The integration tests are a more comprehensive suite of tests. They
diff --git a/synapse/storage/engines/sqlite.py b/synapse/storage/engines/sqlite.py
index 3b1b19c00e..316e188dc9 100644
--- a/synapse/storage/engines/sqlite.py
+++ b/synapse/storage/engines/sqlite.py
@@ -21,6 +21,7 @@
 import platform
 import sqlite3
 import struct
+import sys
 import threading
 from typing import TYPE_CHECKING, Any, Mapping
 
@@ -90,6 +91,20 @@ class Sqlite3Engine(BaseDatabaseEngine[sqlite3.Connection, sqlite3.Cursor]):
         # We need to import here to avoid an import loop.
         from synapse.storage.prepare_database import prepare_database
 
+        if sys.version_info >= (3, 12):
+            # Opportunistically disable the SQLITE_DBCONFIG_DEFENSIVE
+            # flag on the database, as some of our database migrations
+            # alter the schema and this is forbidden in defensive mode.
+            #
+            # This is only known to be necessary on macOS, though SQLite can
+            # in theory be configured to be defensive by default on any
+            # platform.
+            #
+            # The constant for this is only exposed in the sqlite3 module
+            # on Python >= 3.12.
+            assert isinstance(db_conn.conn, sqlite3.Connection)
+            db_conn.conn.setconfig(sqlite3.SQLITE_DBCONFIG_DEFENSIVE, False)
+
         if self._is_in_memory:
             # In memory databases need to be rebuilt each time. Ideally we'd
             # reuse the same connection as we do when starting up, but that