Following an extended shakedown cruise[6] in the Caribbean and a post-shakedown yard period, Seal departed New England in late November and proceeded to the Panama Canal Zone to commence operations out of her home port, Coco Solo.

Arriving on 3 December, she conducted local operations off Balboa, Panama, and off Coco Solo into January 1939, then proceeded to Haiti where she participated in type exercises prior to Fleet Problem XX.

In June, the submarine again sailed south, transited the Panama Canal, and continued on to San Diego, California, and Pearl Harbor.

Departing Pearl Harbor on 24 October, she reached Manila on 10 November, and 34 days later, cleared that bay to commence her first war patrol.

She headed north to intercept Japanese forces moving into northern Luzon to reinforce those already landed at Vigan and Aparri, Cagayan.

From the Vigan area, the submarine moved into the approaches to Lingayen Gulf, and in January 1942, she again turned north to patrol the entrance to Lamon Bay.

Daily air raids necessitated diving during the day and precluded repairs to her engines, which smoked excessively, and to the broken prism control mechanism in her high periscope.

During the early morning hours of 28 May, she entered the South China Sea, and that night, she fired on and sank 1,946-ton Tatsufuku Maru.

On 7 June, while off Cam Ranh Bay, she attacked an eight-ship convoy and underwent a seven-hour depth charging by surface ships and aircraft.

Despite 11 sightings, she was plagued by uncertain torpedo performance against shallow draft vessels, by premature explosions and by leaky exhaust valves and holes in the fuel compensating line which resulted in air and oil leaks to the surface.

Captured Japanese documents later confirmed the sinking of 3,500-ton Boston Maru by an American submarine on that date in that location.

On 31 July, while the submarine was diving, the conning tower hatch failed to latch, and subsequently flew open.

Substantial damage to her electrical circuits resulted and Seal retired eastward to make temporary repairs.

During her next war patrols, Seal provided lifeguard services and conducted reconnaissance missions—at Kwajalein on her ninth - from 7 November-19 December - and at Ponape on her tenth - from 17 January-6 March 1944.

With 14–15 hours of daylight, she hunted in the coastal and inter-island shipping lanes to Muroran, Matsuwa, and Paramushiro.

On the night of 8 September, she encountered a two-column, six-ship convoy with an escort on each wing, and closed in to the leading ship.

On 25 October, she caught and sank Hakuyo Maru (5,742 GRT) killing 1,415 as it ran down the convoy lanes away from Paramushiro.

Seal arrived at Pearl Harbor on 29 November, and after refit, assumed training duties in the Hawaiian area.

In June 1945, she returned to New London where she continued her training duties through the end of World War II.