USS S-16 (SS-121) was a second-group (S-3 or "Government") S-class submarine of the United States Navy. Her keel was laid down on 19 March 1918 by the Lake Torpedo Boat Company in Bridgeport, Connecticut. She was launched on 23 December 1919 sponsored by Mrs. Archibald W. McNeil, and commissioned on 17 December 1920, Lieutenant Commander Andrew C. Bennett in command. She was decommissioned on 4 October 1944 and struck from the Naval Vessel Register. S-16 was intentionally destroyed by sinking on 3 April 1945, off Key West, Florida.