The following January, 1924, she returned to the Panama Canal Zone and the Caribbean Sea for further fleet problems and exercises and then operated primarily off southern California into 1926.

The previous year, 1925, Division 16 had been transferred to the Asiatic Fleet, and, in November 1926, S-33 moved west to join her sister ships at Cavite.

That summer, increased United States involvement in World War II brought activation orders, and, on 16 October 1940, S-33 was recommissioned.

Toward the end of 1941, however, her operational area was extended, and she moved up to the Newfoundland coast to test S-boat capabilities under high latitude conditions.

She returned to New London after the entry of the United States into World War II and at the end of December 1941, proceeded to Philadelphia for an overhaul.

In June 1942, she proceeded on to San Diego, California, and, toward the end of the month, moved north to the Aleutian Islands.

She sighted three enemy ships, but Japanese antisubmarine measures, surface and air, prevented her attacking the first two targets and fog saved the third.

Poor visibility, rough seas, and slow speed hindered hunting during her fifth war patrol, conducted in the Kiska area from 15 October to 11 November.

She conducted her ninth and last war patrol, a photographic reconnaissance of Buldir and Kiska Islands, from 14 July to 9 August 1943, then got underway to return to California.

A fictional version of S-33 is depicted as part of the United States Atlantic Fleet in 1942 in the 2000 film U-571, starring Matthew McConaughey, Bill Paxton, and Jon Bon Jovi.