Following her return to New London on 10 April 1939, she sailed with sister ships Snapper and Salmon for the Pacific, transited the Panama Canal on 25 May, and arrived at San Diego, California, on 2 June.

Following her return to San Diego, Skipjack underwent overhaul at the Mare Island Navy Yard in Vallejo, California, and then proceeded back to Pearl Harbor, where she was attached to Rear Admiral Wilhelm L. Friedell's COMSUBPAC, Pacific Fleet, as a member of SubDiv 15 (commanded by Captain Ralph Christie).

Skipjack's second war patrol, conducted in the Celebes Sea, was uneventful with the exception of an unsuccessful attack on a Japanese aircraft carrier.

Finding herself almost dead ahead, Skipjack fired a "down the throat" spread of three torpedoes that sank Kanan Maru (Japanese: 河南丸).

Two days later, the submarine intercepted a three-ship convoy escorted by a destroyer and she fired two torpedoes that severely damaged the merchant ship, Taiyu Maru (Japanese: 大有丸).

[10][11] Following participation in performance tests for the Mark 14 torpedo, Skipjack sailed for her fourth war patrol on 18 July 1942, conducted along the northwest coast of Timor which she reconnoitered and photographed.

On 14 October, while patrolling south of the Palau Islands, the submarine torpedoed and sank the 6,781-ton cargo ship, Shunko Maru (Japanese: 春光丸).

On 26 January 1944, she commenced a night attack on a merchant ship, but, prior to firing, she shifted targets when an enemy destroyer began a run on the submarine.

After returning to Pearl Harbor, Skipjack got underway for her tenth and final war patrol, conducted in the Kuril Islands area.

Skipjack was later sunk as a target vessel in the second atomic bomb test at Bikini Atoll in July 1946 and was later raised and towed to Mare Island.