She was launched on 23 April 1921, sponsored by Mrs. Joseph E. Austin, and commissioned at Bridgeport on 6 June 1922 with Lieutenant Ingram C. Sowell in command.

Seven minutes later, just as a pilot cell cover was removed to test the specific gravity of the electrolyte, the forward battery exploded.

On 12 March 1927 she returned to New London, from which she completed a run to Portsmouth, New Hampshire, and back before proceeding to Philadelphia, Pennsylvania, with S-50, for inactivation.

[1] The U.S. Navy apparently reacquired S-49 about 1941 at Baltimore "as equipment" for use in experimental work at the Naval Mine Warfare Proving Ground, Solomons, Maryland.

[1] During this work, she sank on 16 December 1942 in 102 feet (31 m) of water in the Patuxent River at 38°19′53.2″N 076°29′17.2″W / 38.331444°N 76.488111°W / 38.331444; -76.488111 (USS S-49) on a bearing of 318.5 degrees true, distant 525 yards (480 m), from the southern tip of Point Patience, Maryland.