Attached to SubDiv 18, S-15 departed New London, Connecticut, on 31 May 1921, and sailed via the Panama Canal, California, Hawaii, and Guam to the Philippines.

Sailing from Manila on 15 May 1923, S-15 visited Shanghai, Yantai, and Qinhuangdao before returning via Wusong and Amoy to Cavite on 11 September.

Departing Cavite on 29 October, she arrived at Mare Island Naval Shipyard, California, on 30 December.

Following voyages to Bermuda, she operated at Saint Thomas, United States Virgin Islands, from 31 October to 9 December 1941; in the Panama Canal area from January 1942 into December 1943; at Guantanamo Bay through May 1944; in the Panama Canal area from June through September; at Trinidad for the rest of the year; and at Guantanamo from January into March 1945.

S-15 was one of the only five submarines (along with her sisters S-14, S-16, S-17 and S-48) built by the Lake Torpedo Boat Company to see service in World War II.