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.
Sendai, accompanied by the destroyer Shikinami, had been following the Americans, but 16" projectiles drove them off. Soon after, however, the battle was rejoined. The Japanese force had been dispersed and within minutes of the battleship-cruiser encounter, enemy destroyers, edging along the southern shore of Savo, entered the fray. Benham and Preston followed. Gwin, which had been firing illumination shells toward the earlier gunfire exchange, came into the action in time to sight the cruiser Nagara and 4 destroyers closing in. Farther out, heavier Japanese ships were preparing to join in. The concentrated American destroyers were now central targets.
Approximately 8 minutes after the enemy was engaged, Walke was hit. Soon after, Preston, preparing her torpedoes, was struck. One salvo from Nagara had put both firerooms out and toppled the after stack. Her fires made an easier target and shells came in from both port and starboard. The fires spread. At 2336, she was ordered abandoned. Seconds later she rolled on her side. She floated for another 10 minutes, bow in the air; then sank, taking 116 of her crew with her.
The battle continued. Gwin now became the target of Japanese guns. Shells exploded in an engine room and on the fantail. At 2338, Walke's forecastle was blown off. Benham's bow was all but demolished; she would go down on the 15th. Walke, burning brightly, soon followed Preston to the Savo Island graveyard. At 2348, as the battleships took over, the remaining destroyers were ordered to retire. In the ensuing duel, Washington inflicted irreparable damage on the Japanese bombardment force and remained unscathed. South Dakota however, was exposed by searchlight and took shells from that enemy force. The Japanese had again scored heavily, but in doing so had lost a battleship and a destroyer, and, more important, had abandoned their mission of bombarding Henderson Field into uselessness.
Preston (DD-379) earned two battle stars for World War II service.