Pompano's engines were a complete failure and were wrecked during trials before even leaving the Mare Island Navy Yard.

Reaching port shortly after the attack, she sailed from Pearl Harbor on 18 December 1941 for her first war patrol, devoted mainly to reconnoitering the eastern Marshall Islands for an aircraft carrier strike in January.

[13] Pompano arrived off Wake Island on 1 January 1942 to gather intelligence, approaching close enough to see Japanese machine gun posts.

On her next patrol, to Japanese home waters, Pompano left Pearl Harbor on 20 April 1942 (with a load of older Mark 10 torpedoes,[18] due to production shortages at Newport Torpedo Station), refueled at Midway Island, and entered her area 7 May patrolling the sea lanes west of Okinawa and in the East China Sea.

On the next day, after chasing for seven hours and fighting a motor fire in the process,[18] she torpedoed Tokyo Maru, which exploded and sank.

As Pompano shifted her patrol area to the main route between Japan and the East Indies, a large transport escorted by one destroyer caught her eye on 30 May.

Running to a position ahead of the convoy, she waited until her victim was only 750 yd (690 m) away, scoring solid hits (with two more Mark 10 torpedoes)[18] which sank Atsuta Maru two and a half hours later.

On 5 June, while on the shipping route between Japan and the Mariana Islands, the submarine caught a trawler and sank it with gunfire.

[19] After a refit - and a change of command, to Willis M. Thomas - she sailed from Pearl Harbor again on 19 July, bound for Japan, on her third war patrol.

After running aground twice while attempting to escape, wiping off the sonar heads[20] and with her battery almost exhausted, she surfaced, determined to fight on, only 1,000 yd (910 m) from shore, evaded the ashcan and hastily cleared the area.

Firing two torpedoes, Pompano's men heard two very loud explosions, and saw a huge column of spray and water through the periscope, blotting out the destroyer's bow at 700 yd (640 m).

The last attack of the patrol came while en route Midway when, on the 500-mile (800 km) circle from Tokyo, Pompano sighted Naval Auxiliary 163 lying to.

During the entire patrol, with 26 days on station, she sighted only four torpedo targets, one of them a submariner's dream, an aircraft carrier, identified as Shokaku.

Pompano fired six torpedoes at long range 4,000 yd (3,700 m), and was credited with damage for 28,900 tons (denied postwar).

[note 5] She made only one other attack, spent two-thirds of the patrol fighting rough weather, and returned to Midway on 5 May, then to Pearl Harbor five days later.

Stopping briefly at Midway to top up supplies, she entered her area on 19 June, patrolling across traffic lanes from Japan to the south.

Two days after that, an ill-advised long shot at a three-ship convoy also missed, while on 10 July, a tanker escaped thanks to two erratic Mark 14s.

The enemy made no anti-submarine attacks during this period in Pompano's area, so newly-laid mines in the vicinity, not known to U.S. Navy intelligence until after she sailed,[25] probably sank her.

However Japanese records show that a submarine was sunk on 17 September by air attack off the Aomori Prefecture near Shiriya Zaki.

Although the fate of the Pompano has been unknown for years, new evidence from Japan suggests it may have been hit by depth charges from members of the Japanese Navy following an oil slick on top of the water — which they took as an indication there was a submarine below.

A possibility is that she was sunk on 17 September 1943, by a bomb and depth-charge attack in the Shiriyasaki Sea, off Aomori Prefecture, at northeast Honshu Island, by a Japanese seaplane and surface vessels.

; Also see: Holmes, Wilfred J., Double-Edged Secrets: U. S. Naval Intelligence Operations in the Pacific during World War II, p. 156; Hackett, Bob and Sander Kingsepp and Peter Cundall, "IJN Minelayer ISHIZAKI: Tabular Record of Movement," published online at http://www.combinedfleet.com/Ishizaki_t.htm (accessed on 11 October 2011); Miller, Vernon J., "U. S. Submarine Losses," issue 44, p. 46.)