USS S-46, a 1126-ton S-42 class submarine built at Quincy, Massachusetts, was commissioned in June 1925. She was based at Coco Solo, Panama Canal Zone during 1925-1927, taking occasional cruises out of that area to participate in special training and major U.S. Fleet maneuvers. In June 1927, S-46's home port was shifted to San Diego, California, and in 1930 to Pearl Harbor, Hawaii. Her peacetime pattern of training and exercises continued during that time, and after she returned to the Panama Canal Zone in 1936.

S-46 generally remained in the Panama area until after the United States entered World War II, though she did operate in New England and Bermuda waters for a several months in 1941. In March 1942 she was sent west to take an active part in the war with Japan. She departed Brisbane, Australia, in May on a war patrol to the New Britain area, where she hunted enemy shipping without success until mid-June. Two other patrols followed, one to the Solomon Islands in July and August and the second, in September and October, to defend eastern New Guinea. By this time, it was clear that eldery submarines like S-46 had grave difficulties making combat patrols in tropical waters, and in November 1942 she headed back to the United States for an extensive overhaul.

In September 1943, following completion of this work, S-46 went to the North Pacific for operations out of Dutch Harbor, Aleutian Islands. She made two more war patrols, into the waters off Northern Japan, between October 1943 and January 1944, and damaged a Japanese ship during the first. After the end of the second patrol, S-46 was assigned to anti-submarine training. Based at San Diego, she was active in this role until soon after Japan's surrender. Decommissioned in early November 1945, USS S-46 was sold for scrapping a year later.