In addition to patrolling in the Atlantic and Mediterranean, Gregory carried passengers and supplies to the Adriatic and aided in the execution of the terms of the Austrian armistice.

After six months of this duty, the flush-deck destroyer joined naval forces taking part in relief missions to the western Mediterranean 28 April 1919.

A year of local training operations out of the southern port ended 12 April 1922, when Gregory entered the Philadelphia Navy Yard.

As war broke again over Europe, threatening to involve the United States, Gregory and three other four-stackers were taken out of mothballs for conversion to high-speed transports.

Departing Nouméa on 31 July 1942, Gregory joined Task Force 62 (TF 62) (under Admiral Frank Jack Fletcher) and steamed for Guadalcanal.

The night was inky-black with a low haze obscuring all landmarks, and the captains decided to remain on patrol rather than risk threading their way through the dangerous channel.

At 00:56 on 5 September, Gregory and Little saw flashes of gunfire which they assumed came from a Japanese submarine until radar showed four targets; apparently a cruiser had joined the three destroyers.

Fleet Admiral Chester Nimitz, in praising the courageous crews after their loss, wrote that "both of these small vessels fought as well as possible against the overwhelming odds ... With little means, they performed duties vital to the success of the campaign."

[1] Petty Officer First Class Charles French swam 6–8 hours in shark-infested waters near Guadalcanal while towing a life raft with 15 of the Gregory's survivors to avoid capture and possible execution by Japanese forces on land.