After shakedown, the squadron joined the North Atlantic Neutrality Patrol where, south of Iceland on 17 October 1941, Kearny became the first US warship torpedoed by a German U-boat. She survived.
In the spring of 1942, DesDiv 22 was detached to form the screen for Hornet (CV 8) for her move to the Pacific. Three of the four destroyers were lost in 1942–43 (see Destroyer Division 22 for details).
Roe and Division 21, meanwhile, remained in the Atlantic. In November 1942, all five ships participated in the invasion of North Africa.
Operating independently, Roe went to the Mediterranean for the invasion of Sicily in July 1943. There, on the 10th, she collided with Swanson and returned to New York, where she was under repair until September. In 1944, she was transferred to the Pacific, where she joined the Seventh Fleet for operations along New Guinea’s north coast and then a range of assignments with the Fifth and Third Fleets while attached to DesRon 4.
Division 21 spent 1943 in patrol duty off Brazil and in the Caribbean Sea and escorting convoys between the East Coast and North Africa. In 1944, it went to the Mediterranean, where assignments included support for the landings at Anzio, Italy in January and at southern France in August. Convoy duty in the Atlantic resumed through V-E Day in May 1945. Ships of the division then moved to the Pacific, where they were in training at Pearl Harbor when the war ended.