Mustin sailed on 17 August with TF 17, the Hornet group, bound for an important role in the great sea warfare which wrested the Southwest Pacific from the Japanese.

In the Battle of the Santa Cruz Islands on 26 October, Mustin rescued 337 of Hornet's survivors, and had the grim duty of destroying the heavily damaged carrier with a full salvo of torpedoes.

After covering the American recapture of Kiska on 15 August, Mustin headed for a Mare Island Naval Shipyard overhaul, from which she returned to Pearl Harbor on 31 October.

Mustin sortied with TF 52 on 10 November for the assault on Makin in the Gilberts 10 days later, then returned to the west coast for rehearsal amphibious operations off San Pedro, California.

Mustin next joined the support force of powerful TF 58, protecting vital fleet oilers as the carriers and planes they fueled struck Palau, Yap, Woleai, and Ulithi in the Carolines on 30 March – 1 April.

The continuing operations on and around New Guinea gave Mustin varied duty, on escort, patrol, bombardment, and as fighter-director, as one landing after another moved up the coast to wrest the huge island from the enemy.

After rehearsals off New Guinea, Mustin sortied for the assault on Luzon on 9 January 1945, and for the next month fired in support of land forces, joined in repelling enemy air attack off Lingayen, and made antisubmarine patrols.

She operated in the Philippines, aiding in movement of reinforcements until 2 February, when she sailed for Guadalcanal, off which she joined the 5th Fleet, serving as antisubmarine patrol ship while awaiting the beginning of the rehearsals for the Battle of Okinawa.

Late in the year she returned to the west coast and sailed back to Hawaii to prepare for Operation Crossroads, the atomic tests at Bikini Atoll, in which she was engaged through the summer of 1946.