Admiral Charles A. Lockwood had earlier relieved Hutchinson of command of the submarine USS Grampus (SS-207) for lacking aggressiveness.

After recommissioning and fitting out in New Orleans, the new submarine trained in the Bay of Panama, departed Balboa 8 August 1943, and arrived at Brisbane, Australia, on 11 September.

On her first war patrol, 24 September through 24 November 1943, Rasher operated in the Makassar Strait–Celebes Sea area, and sank the passenger-cargo ship Kogane Maru in a submerged attack at dawn on 9 October.

A midnight attack on a second convoy in the Makassar Strait off Mangkalihat Peninsula resulted in a hit on a tanker, but vigorous countermeasures by enemy destroyers prevented any assessment of damage.

[8] Following refit, Rasher commenced her second war patrol on 19 December 1943 and hunted Japanese shipping in the South China Sea off Borneo.

A mushroom-shaped fire rose as the last two torpedoes struck, and Kiyo Maru sank, leaving an oil slick and scattered debris.

First she sank the cargo ships Tango Maru, killing thousands of Imperial Japanese Army soldiers, Javanese rōmusha forced laborers, and Allied prisoners-of-war.

Later in the same attack she sank Ryusei Maru, killing up to 5,000 of her complement of Japanese Army soldiers, Indian prisoners of war, and rōmusha forced labourers.

On 19 March 1944, Rasher sighted the Japanese submarine Ro-112 as Ro-112 was surfacing in the Java Sea north of Bali off Cape Bungkulan at 08°02′S 115°25′E / 8.033°S 115.417°E / -8.033; 115.417.

Thirty miles south of Scarborough Shoal at 2255 5 August, Rasher launched a spread of six bow torpedoes[11] at the largest ship in a three-ship convoy.

[12] Rasher observed nine successive aircraft contacts to the north on the afternoon of 18 August and deduced these were air patrols for an important convoy.

[11] Rasher followed the group moving northwest while Bluefish intercepted the remaining ships continuing southwesterly and sank two tankers.

[11] Rasher launched four bow torpedoes at a range of 2,200 yards (2,000 m), and three hits on the cargo-transport Eishin Maru[13] caused an ammunition detonation with the pressure wave sweeping over the submarine's bridge.

[11] Postwar accounting verified Rasher had sunk the highest tonnage of any World War II U.S. submarine patrol to that date.

Her sixth patrol, as a unit of a wolfpack with Pilotfish and Finback, commenced on 29 January, and was conducted in the southern sector of the East China Sea.

Rasher was credited with sinking 99,901 tons of Japanese shipping, the third highest total for US submarines in World War II.

However, a Japanese destroyer credited as sunk by sister ship USS Flasher (SS-249) is given a name that never existed and may have been a case of mistaken identity.

Prior to and following a second WestPac deployment from 4 March to 4 September 1958, SSR-269 served in Fleet exercises as an early warning ship, and in ASW training operations.

Involved in maintaining fleet readiness until mid-August 1962 when she deployed to WestPac, Rasher continued to exhibit her usual high standards of performance.

Her next deployment, beginning on 3 August 1964, involved support of 7th Fleet operations off Vietnam, as well as ASW exercises with SEATO allies.

Her next WestPac deployment, from 3 January to 17 July 1966, included amphibious and ASW training support for Republic of Korea, Nationalist Chinese, and Thai units, as well as operations with the 7th Fleet off Vietnam.

Rasher spent the remainder of her commissioned career providing training services off the coast of California to UDT and ASW units.