After a lengthy shakedown cruise she was attached to the Pacific Fleet. She was in port on December the 7th in Pearl Harbor, but survived the attack without any damage, and shot down one attacker. She immediately steamed out in search for the Japanese Fleet, with no results. In the following months she supported the early carrier-based Navy airstrikes on Bougainville, Salamaua and Lae. She escorted the Saratoga in the Solomon-landings, and took part in the battle off Savo Island. She spent the rest of 1942 in escort duties, returning for overhaul to Oahu in December. She supported the invasion of the Attu-atoll, but in the stormy weather she collided with the destroyer minelayer USS Sicard (DM-21), and returned to port for needed repairs.

After she took part in the invasion of the Gilbert Islands and the Marshalls, and later she was engaged in screening duties around Truk, and on 30 April, 1944 together with two other US ships she attacked and sunk the Japanese submarine RO-45. In the rest of the war she took part in almost every major engagement, like the battle around the Marianas, the Philippine Sea and Leyte Gulf.

She finished the war in escort duties, and was decommissioned on 22 October 1945, stricken 1 November 1945 and sold for scrap on 20 December 1946.

USS Macdonough was awarded 13 Battle Stars for her services in WW2.