Following shakedown, Preston operated briefly under the Chief of Naval Operations, then joined Battle Force, U.S. Fleet. Initially assigned to DesRon 2, then shifted to DesRon 5, she conducted peacetime training exercises in the Pacific until 7 December 1941. Patrol and coastal escort duties along the west coast kept Preston in the eastern Pacific until 1 June 1942. Then setting a westward course she headed for Hawaii in the screen of Saratoga. Arriving on the 6th, her group, TG 11.1, departed again the next day to rendezvous with TF 17 and deliver planes, pilots, and material to Enterprise and Hornet as that force refueled and rested after the Battle of Midway.

On the 13th, Preston returned to Pearl Harbor and for the next four months conducted type exercises and performed patrol and escort work in the Hawaiian area. She joined TF 16, 4 October, and on the 15th sailed for the Solomons. On the 24th, TF 16 rendezvoused with TF 17, formed TF 61 and continued on. Two days later, Preston, in the carrier screen, introduced her guns to the enemy at the Battle of the Santa Cruz Islands. Splashing two planes, she emerged unscathed from her first engagement and retired to Nouméa. Rearmed, she headed back to the Solomons and her second and last, fight.

On the evening of 14 November, Preston, with TF 64, sailed along the western end of Guadalcanal to intercept another Japanese run down the "Slot" to bombard Henderson Field and land reinforcements. Swinging around Savo Island, the force, two battleships preceded by four destroyers, entered the channel between Savo and Cape Esperance. At 2300, the battleship Washington picked up the enemy cruiser Sendai on her radar, and, at 2317, the 3rd Battle of Savo Island began. (continued)