After the United States entered World War II, Stack continued to patrol in the Caribbean until 22 December when she was assigned to escort Wasp from Bermuda to Norfolk, Virginia.

En route from Hvalfjörður to Reykjavík, Iceland, on 29 January, she was ordered on a submarine sweep after the USCGC Alexander Hamilton, operating with Task Force (TF) 15, was torpedoed.

Arriving on 18 July, the ships spent five days preparing for battle, and sailed for the invasion of Guadalcanal, Solomon Islands.

Stack covered the Guadalcanal-Tulagi landings with Destroyer Squadron (DesRon) 12 and was then assigned independent escort and patrol duty in the Guadalcanal area.

Following repair, overhaul and sea trials, she sailed on the 23d to escort SS Matsonia to Pearl Harbor and continue on to Efate, New Hebrides Islands.

On the night of 6 and 7 August, in what would be known as the Battle of Vella Gulf, Stack, with other units of Task Group (TG) 31.2, was searching for enemy traffic along Gizo and Kolombangara island.

Stack then steamed west of the Gilberts to participate in the combined aerial and shore bombardment of Nauru Island on 8 December 1943.

In late January and early February 1944, Stack, as part of TF 58, participated in the bombardment and assault on Kwajalein and Majuro Atolls in the Marshalls.

On 17 and 18 February, the task force, now including nine carriers, carried out raids against the Japanese bastion at Truk and, on the 20th, against Jaluit Atoll.

She was overhauled and held sea trials from 11 March to 22 June when she weighed anchor for Pearl Harbor and Milne Bay.

On the 20th, she, in company with Lang and five YM's, performed mine sweeping operations and provided antiaircraft support for landings in the Philippines on Pinaon Island.

Stack, with TG 78.5, sortied from Sansapor, New Guinea, on 30 December 1944 bound for Lingayen Gulf to support the assault and landing at "Blue Beach", Luzon.

On 8 February 1945, Stack departed San Pedro for the Solomon Islands and a period of upkeep, training, logistics, and exercises which were to last until mid-March.

Stack arrived off Okinawa on 1 April, "L-Day", and began her assigned duties as an antisubmarine and antiaircraft patrol ship.

Stack had boiler trouble en route which forced her to undergo tender availability at Pearl Harbor until late July.

On 28 August, she was en route from Guam to Truk Atoll with Brigadier General Leo D. Hermle, USMC, and various other Navy and Marine Corps officers on board for a preliminary conference with Japanese military authorities regarding the surrender of their forces.

She was assigned to Joint Task Force 1 as a target for Operation Crossroads, the atomic bomb tests to be held in the Marshall Islands.