Following shakedown along the California coast, Seahorse sailed to Pearl Harbor, Territory of Hawaii and, on 3 August 1943, got underway for her maiden war patrol, conducted off the Palau Islands.

During this patrol, Seahorse's commanding officer ignored several potential targets, rather than face sonar-equipped escorts,[7] which unrealistic prewar training indicated was virtual suicide.

Early on the morning of 2 November, following an attack on the convoy by another United States submarine, Seahorse evaded three escort ships and launched three torpedoes into two freighters.

On 22 November, Seahorse maneuvered past three enemy escorts, launched four torpedoes from periscope depth, and sank the cargo ship, Daishu Maru.

The results seemed disappointing—until a sudden blast sent flames and debris mushrooming high into the air, completely destroying the 7,309-ton tanker, San Ramon Maru.

After evading the escorts, she surfaced in time to see the results of her latest attack as the cargo ship, Toei Maru, slipped beneath the waves.

Shortly thereafter, her second spread of torpedoes damaged the cargo ship Kizugawa Maru, which subsequently was towed to Apra Harbor on Guam for repairs.

Although a counterattack by escorting destroyers drove Seahorse from the vicinity, she quickly regained contact and continued the chase into the following day, sinking the cargo ship Bisaku Maru.

91 en route from Takao to Hong Kong consisting of four transport/cargo ships and two escorts (the Momi-class destroyer Kuri and the Chidori-class torpedo boat Hatsukari).

The convoy's only remaining transport, Gyoun Maru (the ex-British Ethel Moller), and its two escorts, were able to reach Hong Kong without further incident on 5 July.

Upon completion of an overhaul at Mare Island Navy Yard, Seahorse put to sea on 9 March 1945 for her seventh war patrol.

On 18 April, an attack by two patrol boats (CD-14 and CD-132) left the submarine's interior a shambles of broken glass, smashed instruments, and spilled hydraulic oil.

She was reclassified an auxiliary submarine, AGSS-304, on 6 November 1962, struck from the Navy list on 1 March 1967, and sold on 14 December 1968 to Zidell Explorations Inc., Portland, Oregon, for scrapping.