After conducting shakedown out of New London, Guardfish left that base on 28 June 1942 for Pearl Harbor via the Panama Canal, and arrived there on 25 July to prepare for her first cruise.

Moving her base of operations to the Truk area, Guardfish left Pearl Harbor on 2 January 1943 to patrol off the Japanese stronghold.

Her fourth war patrol was conducted in the Bismarcks, Solomons, and New Guinea area, and Guardfish recorded no kills on this cruise, 9 March to 30 April 1943.

Leaving Brisbane for the same waters on 25 May 1943, Guardfish sank the transport and hell ship, Suzuya Maru,[7] and damaged another before being forced to dive by aircraft on 13 June.

Guardfish left Brisbane for her sixth war patrol on 24 August 1943, landing a reconnoitering party on Bougainville and then moving into cruising waters.

[8] Turning to the shipping lanes between Truk and Guadalcanal, Guardfish began her seventh war patrol on 27 December 1943, sinking 10,024 ton oiler Kenyo Maru on 14 January 1944.

After serving briefly as lifeguard ship off Truk she arrived at Pearl Harbor 18 February and from there returned to San Francisco for repairs nine days later.

She then joined submarines Thresher, Piranha, and Apogon to form the coordinated attack group known as the "Mickey Finns", commanded by Captain W. V. O'Regan in Guardfish.

After damaging another freighter 18 July, Guardfish sank the 6,512 GRT cargo ship Teiryu Maru the next day, barely escaping the attacks of her escorts.

Sailing the Sea of Japan as a member of another wolf pack on 23 August 1944, Guardfish and the submarines, Thresher and Sunfish, had a 40-minute surface gun battle with sampans on 2 September.

Guardfish left on 26 November 1944 for her 10th war patrol to cruise in the "Convoy College" area of the South China Sea, with yet another wolf pack.

She recorded no sinkings on this cruise, but nearing Guam in the early morning of 24 January 1945 she mistook the U.S. Navy rescue and salvage ship Extractor (ARS-15), for a Japanese I class submarine.

Guardfish's 11th war patrol was spent watching for enemy fleet units attempting to escape from the Inland Sea of Japan by way of the Kii Suido between Shikoku and Honshū.

Guardfish left Midway on 8 May 1945 on her 12th and final war patrol, and was assigned lifeguard station for the ever-increasing air attacks on the Japanese mainland.

), describes the Guardfish, either the 1st or 2nd war patrol and Commander Klakring's famed sneak into Tokyo Bay; Close enough to watch the horse races through the periscope.