Moffett left Newport, her base for Atlantic Fleet operations between 1936 and 1941, 24 April 1941 to join the South Atlantic Neutrality Patrol off Brazil. After the fall of France, she operated out of Puerto Rico with a force guarding against hostile action by the French West Indies fleet based at Martinique and Guadeloupe under a Vichy inclined admiral. She left her South Atlantic duty in August 1941 to protect Augusta carrying President Franklin D. Roosevelt to the Atlantic Charter Conference with Prime Minister Winston Churchill at Argentia, Newfoundland.
For the first two years of World War II, Moffett operated with typical destroyer versatility on patrol and convoy duties in the South Atlantic and Caribbean, escort missions bringing her to U.S. ports from time to time. She made several voyages to west African ports in 1943. On 17 May 1943, as she and Jouett were on escort duty in the Caribbean, she learned that patrol planes had spotted and fired on a German submarine. At 1246 Moffett sighted the U-boat. The two destroyers sank the submarine—U-128—with 5-inch gunfire, then rescued 50 survivors including the commanding officer.
Three months later, while escorting Memphis and a merchant ship to Ascension, Moffett made contact with U-604 and again Joined Navy aircraft to attack. A running fight ensued through the night, and when the submarine surfaced 95 miles north of Trinidad next morning, Moffett drove her down once more with five hits. Three days later, with the aid of aircraft, contact was regained and the submarine badly damaged by Moffett's depth charges. In the dark and confusion of action, a friendly aircraft mistaking Moffett for the enemy made two strafing runs which caused minor damage. The stricken submarine was finally scuttled by her crew 11 August; Moffett was credited with the kill.
On 26 March 1944, Moffett sailed as escort commander of Convoy YN-78, a group of tugs barges, and patrol craft en route England for the invasion of Normandy. After visiting Wales and Northern Ireland, Moffett returned to New York 11 May.
Moffett’s last combat experience came 1 August, when enemy planes attacked Convoy UGS-48 as she screened it en route Bizerte. Laying smoke to protect the convoy, Moffett went into a series of brilliant tight turns and maneuvers to dodge the torpedo panes which continued to attack through the night, and with other escorts drove them off with antiaircraft fire. She returned to New York from this mission 27 August. After a last escort voyage to Oran in April 1945, Moffett began extended repairs at Boston.
Towed to Charleston, S.C., 28 May for further repairs, Moffett was still in the yard at the close of the war in August, and work was stopped. She decommissioned in Charleston 2 November 1945 and entered the Reserve Fleet. Stricken from the Navy list 28 January 1947, Moffett was sold for scrapping 16 May 1947 to Boston Metals Co., Baltimore, Maryland.
Moffett received two battle stars for World War II service.