On 23 July, she got underway from Pearl Harbor for her maiden war patrol, as a member of a coordinated attack group with Picuda (SS-382) and Redfish (SS-395).

On 19 August, while patrolling in Philippine waters off the northwest coast of Luzon, Spadefish torpedoed and sank her first enemy target the 9,589-ton, passenger-cargo ship Tamatsu Maru.

The submarine finally let go with four stern torpedoes at the destroyer, but the enemy zigged clear and proceeded to depth charge the entire area.

Spadefish terminated her first war patrol at Pearl Harbor on 24 September, having sunk six enemy ships for a total of over 31,500 tons.

On 23 October, she got underway from Pearl Harbor for her second war patrol, in a coordinated attack group with Sunfish (SS-281) and Peto (SS-265).

The unarmored fuel tanks of the escort carrier Shinyo exploded and started a huge fire that destroyed the ship and killed most of her crew.

After spending the holidays at Majuro, Spadefish departed on 6 January 1945 for her third war patrol, conducted with Pompon (SS-267), Atule (SS-403), and Jallao (SS-368) in the Yellow Sea.

The 7,158-ton converted seaplane tender Sanuki Maru, exploded and quickly sank, and the frigate Kume spouted flames and began to sink slowly.

An enemy patrol airplane dropped a depth charge in the vicinity of the submarine; but, although she was rocked by the shock waves, Spadefish was unharmed and returned to Guam on 13 February.

[8] On 23 March 1945, Spadefish sneaked past four escorts and let go with three torpedoes that sank the 2,274-ton cargo ship Doryo Maru.

Spadefish patrolled along the coast of Kyūshū, continuing north to Tsushima Strait, where she carried out reconnaissance to determine the presence of minefields.

Equipped with a new mine-detecting device, she began her fifth war patrol, joining eight other United States submarines in penetrating through the minefields of Tsushima Strait into the Sea of Japan.

Spadefish remained at Pearl Harbor until 2 September 1945 and then set course for Mare Island Naval Shipyard where she was decommissioned on 3 May 1946 and placed in reserve.