diff --git a/changelog.d/18499.bugfix b/changelog.d/18499.bugfix
new file mode 100644
index 00000000000..b07601a35d9
--- /dev/null
+++ b/changelog.d/18499.bugfix
@@ -0,0 +1 @@
+Fix CPU and database spinning when retrying sending events to servers whilst at the same time purging those events.
\ No newline at end of file
diff --git a/synapse/federation/sender/per_destination_queue.py b/synapse/federation/sender/per_destination_queue.py
index b3f65e8237e..8d6c77faee9 100644
--- a/synapse/federation/sender/per_destination_queue.py
+++ b/synapse/federation/sender/per_destination_queue.py
@@ -129,6 +129,8 @@ def __init__(
 
         # The stream_ordering of the most recent PDU that was discarded due to
         # being in catch-up mode.
+        # Can be set to zero if no PDU has been discarded since the last time
+        # we queried for new PDUs during catch-up.
         self._catchup_last_skipped: int = 0
 
         # Cache of the last successfully-transmitted stream ordering for this
@@ -462,8 +464,18 @@ async def _catch_up_transmission_loop(self) -> None:
                 # of a race condition, so we check that no new events have been
                 # skipped due to us being in catch-up mode
 
-                if self._catchup_last_skipped > last_successful_stream_ordering:
+                if (
+                    self._catchup_last_skipped != 0
+                    and self._catchup_last_skipped > last_successful_stream_ordering
+                ):
                     # another event has been skipped because we were in catch-up mode
+                    # As an exception to this case: we can hit this branch if the
+                    # room has been purged whilst we have been looping.
+                    # In that case we avoid hot-looping by resetting the 'catch-up skipped
+                    # PDU' flag.
+                    # Then if there is still no progress to be made at the next iteration,
+                    # we can exit catch-up mode.
+                    self._catchup_last_skipped = 0
                     continue
 
                 # we are done catching up!