She was routed to the west coast and, on 25 July, got underway from San Francisco for Pearl Harbor, to serve in the Pacific against the Japanese in World War II.

On the 28th, she set a surface craft on fire with her main batteries near Kolombangara and then patrolled between that island and Vella Lavella.

The DD then made two escort runs from Tulagi to Purvis Bay during the first part of the month and ended October supporting landings on the Treasury Islands.

On 1 November, Spence participated in the bombardment of Buka and Bonis airfields and of Japanese positions in the Shortland Islands to support the Landings at Cape Torokina, Bougainville.

[1] The destroyer fired a spread of torpedoes at a ship 3,000 yards (3,000 m) away and was rewarded with black smoke pouring from the target.

Since Spence was low on ammunition, she called upon DesDiv 45 to pour shells into the ill-fated destroyer Hatsukaze which sank stern first.

On 24 November, the squadron was refueling in Hathorn Sound when ordered northwest of Buka Island to intercept Japanese shipping which American intelligence had learned would attempt to evacuate aviation personnel from the Buka-Bonis airfields.

Spence operated out of Purvis Bay until late January 1944 when she patrolled near Green Island and Bougainville Strait.

On 5 February, she participated in the bombardment of supply and bivouac areas at Hahela Plantation on the southeast coast of Buka Island.

On the night of 9 and 10 February, Spence helped to shell Tiaraka and Teopasino, Bougainville, Kavieng and Cape St. George, New Ireland.

On the 29th and 30th, the carriers struck enemy shipping and installations at Truk, the powerful Japanese naval base in the Caroline Islands.

The destroyer conducted shore bombardment against Rota, Saipan and Guam from 26 June through the end of the month setting fuel tanks afire and sinking two sampans on the 27th.

She arrived at Eniwetok on 31 October and was ordered to Ulithi in early November, where she was assigned to TG 38.1, the Support Unit for the fast carriers of TF 38.

On 17 December, Spence prepared to refuel and pumped out all of the salt water ballast from her tanks; but rough seas caused the fueling operation to be cancelled.

As the ships wallowed in canyon-like troughs of brine, Spence's electrical equipment got wet from great quantities of sea water taken on board.