The first rescue came as she steamed escorting the Marine forces bound for the occupation of Iceland in July 1941, when she saved fourteen survivors, including four American Red Cross nurses, from a torpedoed Norwegian freighter.

On 16 October, she rescued seven men from a lifeboat, survivors of the British Freighter SS HATASU, a straggler form convoy ON19, sunk a few days previously by U-431.

When the United States entered the war, Hughes guarded merchant shipping in coastal convoys, Caribbean sailings, and from the midocean meeting points to Iceland and New York.

Hughes escorted a convoy to Casablanca, returning to New York, in November and December 1943, and on 4 January 1944, sailed from Norfolk, Virginia, to join the 8th Fleet in the Mediterranean Sea.

From 3 March to 4 April, the destroyer resumed convoy escort duties in north African waters and patrol at Gibraltar, then returned to operate off Anzio until just before the final breakout from the beachhead late in May.

While protecting the eastern flank of the shipping off the beachhead from attack on the night of 19/20 August, she spotted three German E-boats attempting to penetrate the screen, and forced two of them to beach while she sank the third by gunfire.