In early 1942 the urgent needs of the war with Japan caused Mustin to be sent to the Pacific. During the next several months, she escorted convoys from the US to Hawaii, to the south Pacific and to Midway. In August, she accompanied USS Hornet (CV 8) as that aircraft carrier steamed southeastwards to participate in what was to be a long and hard fight to hold Guadalcanal. Mustin generally remained with Hornet until that ship was sunk in the Battle of the Santa Cruz Islands in late October. After that, the destroyer remained active in the Guadalcanal campaign, screening heavy ships, escorting supply vessels and bombarding the Japanese ashore.
After the enemy evacuated Guadalcanal in February 1943, Mustin spent a few more months in the region. She then went north to join in the Aleutians campaign, where she took part in the landings on Attu in May and Kiska in August. During late 1943 and early 1944, the destroyer participated in the campaigns to seize bases in the Gilbert and Marshall Islands. She served with Task Force 58 during its Central Pacific raids in March and April 1944 and became part of the Seventh Fleet soon afterwards. While in the southwest Pacific, Mustin supported the advance across the top of New Guinea, the invasion of Morotai and the Leyte operation.
In January and February 1945, Mustin took part in the invasion of Luzon and other elements of the recapture of the Philippines. She served off Okinawa during April and May, during the hard battle to take that island in the face of desperate resistance ashore and suicide plane attacks at sea.
After the fighting ended, Mustin helped with the occupation of Japan. She briefly visited the west coast in late 1945, then went to Hawaii to prepare for target duty in connection with the July 1946 atomic bomb tests at Bikini Atoll. Contaminated by radiation after that experience, Mustin was decommissioned in August, without leaving the Marshall Islands. She was destroyed as a gunfire target in April 1948.