After shakedown along the New England coast and in Chesapeake Bay, Grayson joined Destroyer Division 22 (DesDiv 22) of the Atlantic Fleet.

After ten months patrolling and escorting convoys in the North Atlantic, Grayson was ordered to the Pacific to join an American fleet battered but resolutely carrying the war to the enemy.

Reaching Guadalcanal via Tongatapu on 7 August 1942, the carriers launched their aircraft to cover the landings there and then operated in the area to block Japanese reinforcements.

Grayson joined Task Force 11 (TF 11), built around Saratoga under Admiral Frank Jack Fletcher.

She remained around Guadalcanal escorting troop transports, patrolling in "The Slot" and served as a radar picket ship.

Returning to Pearl Harbor on 15 April 1943 for overhaul, Grayson continued on to the United States for further repairs and then made to New Caledonia, arriving 24 September.

Grayson returned to Pearl Harbor 1 September 1945, the day of the signing of the Articles of Surrender in Tokyo Bay.