On 19 January 1943, after training from New London, Connecticut, Scamp set course for Pearl Harbor, Hawaii, via the Panama Canal.

She stopped at Midway Atoll in the Northwestern Hawaiian Islands on 5 March 1943, debarked her passenger, Rear Admiral Charles A. Lockwood, Jr., Commander, Submarine Force, Pacific Fleet, fueled, and then headed for the coast of Honshū, Japan.

However, on the afternoon of 28 May 1943, she succeeded in pumping three torpedoes into the converted seaplane tender Kamikawa Maru, which already had been damaged in an attack by the submarine USS Wahoo (SS-238) on 4 May 1943.

At the time, Allied analysts believed that the submarine she sank was I-24, but postwar analysis of Japanese records indicated that it instead was I-168, which had sunk the disabled aircraft carrier USS Yorktown (CV-5) and the destroyer USS Hammann (DD-412) during the Battle of Midway on 7 June 1942.

On 18 September 1943, she attacked a Japanese three-ship convoy and crippled the 8,614-gross register ton passenger-cargo ship Kansai Maru.

On the morning of 21 21 September 1943, Scamp happened upon a heavily guarded Japanese convoy and began to stalk it.

While still maneuvering to attack the convoy, she passed through the wreckage of Kansai Maru and came upon an empty boat containing the sunken ship's logs and other documents.

By the time of the explosion indicating success, Scamp was already in a dive evading a depth charge attack.

On 18 November 1943, Scamp suffered minor shrapnel damage from two bombs dropped by a Japanese floatplane.

On 16 December 1943, Scamp left Brisbane and headed back to the Bismarck Archipelago for her sixth war patrol.

On 14 January 1944, she slipped by two destroyers to launch six torpedoes at the 9,975-gross register ton tanker Nippon Maru.

Foiled in an attempt to return to the area, she headed south to act as plane guard north of Lyra Reef for United States Army Air Forces B-24 Liberator bombers.

Scamp spent her seventh war patrol searching the shipping lanes between New Guinea, Palau, and Mindanao in the Philippines.

Following her resumption of patrol, she battle-surfaced on 4 April 1944 and set fire to a 200-gross register ton trawler, but broke off the action when her deck gun failed.

On 7 April 1944 Scamp encountered six Japanese cruisers escorted by destroyers and planes south of Davao Gulf,.

The diving officer reported that the hydraulic controller had been jarred to "off" in the attack and that the hydraulic plant started closing all the main vents as fire started filling the maneuvering and aft torpedo rooms with a thick, toxic smoke.

She reported her position to be about 150 nautical miles (280 km; 170 mi) north of the Bonin Islands with all 24 torpedoes aboard and 77,000 US gallons (64,000 imp gal; 290,000 L) of fuel remaining.

On 14 November 1944, Scamp was ordered to take up the life guard station off Tokyo Bay in support of U.S. Army Air Forces B-29 Superfortress bomber strikes, but failed to acknowledge the message.