"Mustin" sailed on 17 August with TF 17, the group, bound for an important role in the great sea warfare which wrested the Southwest Pacific from the Japanese. Her group covered the southern approaches to Guadalcanal during the initial phase of fighting there, then struck Buin, Faisi, and Tonolai from the air. 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. She avenged the carrier in part by shooting down five enemy aircraft during the battle.