1921–1935
Departing from New London, Connecticut, on 31 May 1921, S-16 was attached to Submarine Division 18 (SubDiv 18) and proceeded via the Panama Canal, California, the Territory of Hawaii, and Guam, to the Philippine Islands. She arrived at Cavite, Luzon, on 1 December 1921.
S-16 departed Cavite, on 11 October 1922, visited Hong Kong, from 14 to 28 October, and returned to Cavite, on 1 November 1922. Departing Manila, on 15 May 1923, she visited Shanghai, Yantai, and Qinhuangdao, in China, before returning, via Wusong and Amoy, to Cavite, on 11 September 1923. In the summer of 1924, she visited Shanghai, Qingdao, Yantai, and Qinhuangdao, returning to Olongapo, in the Philippines, on 23 September 1924. Departing Cavite, on 3 November 1924, she arrived at the Mare Island Navy Yard, California, on 30 December 1924.
S-16 remained at Mare Island in 1925 and 1926, and operated along the California coast, in 1927, with a visit to Hawaii, in July–August 1927.
From February 1928 until 1935, S-16 served in the Panama Canal area, although she visited Baltimore, Maryland, from 15 May to 5 June 1933. She departed Coco Solo, in the Panama Canal Zone, on 25 January 1935. S-16 was decommissioned at the Philadelphia Navy Yard, on 22 May 1935.
1940–1944
S-16 was recommissioned on 2 December 1940. Following voyages to Bermuda and the Panama Canal Zone, she operated at Saint Thomas, in the US Virgin Islands, from December 1941, during which the United States entered World War II with the Japanese attack on Pearl Harbor on 7 December, to March 1942, then in the Panama Canal area, from April to August 1942.
On 13 July 1942, she was on the surface in the Caribbean Sea, off Panama, when she suffered damage from bombs accidentally dropped near her by United States Army Air Forces planes attacking the German U-boat U-153; the damage prevented her from diving, and she proceeded to port on the surface.
S-16 was based at New London, from September 1942 to June 1944, with operations at Casco Bay, Maine.
