Gwin completed shakedown training on 20 April 1941 and underwent final alterations in the Boston Navy Yard before conducting a neutrality patrol throughout the Caribbean Sea.

On 3 April 1942 Gwin stood out of San Francisco Bay as a unit of the escort for the aircraft carrier Hornet, which carried 16 Army B-25 bombers to be launched in a bombing raid on Tokyo.

Admiral William F. Halsey in carrier Enterprise rendezvoused with the task force off Midway, and General Jimmy Doolittle's famed raiders launched the morning of 18 April when some 600 miles east of Tokyo.

The task force made a rapid retirement to Pearl Harbor, then sped south 30 April 1942, hoping to assist carriers Yorktown and Lexington in the Battle of the Coral Sea.

Gwin departed Pearl Harbor 15 July 1942 to operate in the screen of fast carriers who pounded Japanese installations, troop concentrations and supply dumps as Marines invaded Guadalcanal in the Solomons on 7 August 1942.

The following night the task group found the enemy off Savo Island: the battleship Kirishima, four cruisers, 11 destroyers, and four transports, The Naval Battle of Guadalcanal was intensely fought.

The survivors were landed 20 November at Nouméa, New Caledonia, and Gwin was routed onward to Hawaii, thence to the Mare Island Navy Yard, arriving 19 December 1942.

Immediately after the first wave of troops hit Rendova Beach, Munda Island shore batteries opened fire on the four destroyers patrolling Blanche Channel.

Gwin escorted a reinforcement echelon from Guadalcanal to Rendova, then raced to the "Slot" 7 July to rescue 87 survivors of cruiser Helena, lost in the Battle of Kula Gulf.

The Battle of Kolombangara was joined in the early hours of 13 July and Japanese light cruiser Jintsu quickly slid to the bottom, the victim of smothering gunfire and torpedo hits.

His flagship, Honolulu, cruiser St. Louis and Gwin, maneuvering to bring their main batteries to bear on the enemy, turned right into the path of the "long lance" torpedoes.