Duncan sailed from New York on 20 June 1942 for the South Pacific, arrived at Espiritu Santo on 14 September to join TFs 17 and 18, and with them departed the same day to cover transports carrying the 7th Marine Regiment to reinforce Guadalcanal.

Duncan picked up survivors from the carrier, transferring 701 officers and men to other ships, and 18 wounded and two bodies to the base hospital at Espiritu Santo upon her arrival 16 September.

On 11 October 1942, she was in the screen of Task Force 64 (TF 64) which was assigned to protect a vital transport convoy carrying reinforcements to Guadalcanal.

Contact was made with a large enemy surface force just as the American ships were executing a course change as part of their battle plan.

Destroyer McCalla rescued 195 men from the shark-infested waters and made an attempt to salvage Duncan, but she sank on 12 October 1942, about 6 nautical miles (11 km; 6.9 mi) north of Savo Island.