In January 1940, she visited Newport, Rhode Island, to take on torpedoes and Yorktown, Virginia, to load depth charges before heading for the Gulf of Mexico.

After completing her post-shakedown overhaul, Trippe departed Boston on 24 June ultimately to join the Caribbean portion of the Neutrality Patrol.

For eight months, the destroyer roamed the warm waters of the West Indies to prevent the European belligerents from waging war in the western hemisphere.

After a two-day visit to Norfolk at the end of the first week in January 1941, Trippe steamed south to Guantánamo Bay, Cuba, where she conducted neutrality patrols until spring.

On 24 April, while Trippe continued repairs, President Roosevelt extended the Neutrality Patrol to the very edge of the German war zone.

The puzzled German captain almost perpetrated an incident by attacking; but, unable to match Task Force 1's speed, he gave up the chase late that afternoon.

After more than a month of training and antisubmarine operations off Newfoundland, Trippe departed Argentia on 11 October in company with Yorktown, New Mexico, Quincy, Savannah, and seven other destroyers.

After anchoring briefly at Casco Bay, Maine and patrolling the area between that port and Boston the warships headed for a mid-ocean rendezvous to relieve the Royal Navy escort of a westbound convoy.

On 9 November, she departed the Maine coast in the screen of Ranger, Vincennes, and Quincy to meet another westbound convoy and escort it to the United States.

In mid-November, Trippe escorted Ranger south to the West Indies and screened flight operations conducted from that carrier in the vicinity of Trinidad until early December.

She was returning north with the carrier on 7 December when the Japanese attack on Pearl Harbor jolted the United States into World War II.

Just before dawn on 16 December, an Army bomber approached her from the north and after making several passes dropped a stick of bombs and reported sinking a German destroyer in Block Island Sound.

Her escort duties took her as far south as the Panama Canal and the West Indies, as far north as Newfoundland, and on one occasion, as far east as Londonderry Port in Northern Ireland.

She then screened convoys between that port and Bizerte, conducted patrols, and practiced shore bombardment in preparation to support the Allied landings on Sicily.

On 9 July, the destroyer left Oran in the screen of a Sicily-bound convoy and was still at sea when Allied troops clambered ashore the following day.

When the raid was over, she claimed credit for one of the German eagles Up north, while Lieutenant General George S. Patton's armored columns moved across the northern coast of Sicily and sidestepped heavy enemy formations with amphibious landings, the Navy supported his advance.

The following day, Sicily was declared secured, and Trippe headed north with three PT boats to accept the surrender of the Aeolian Islands of Lipari and Stromboli.

In the early hours of 20 August, Trippe and Wainwright shelled a railroad bridge at Fiume Petrace, then turned south to Bizerte and escorted a convoy to Palermo.

Off Casablanca, they rendezvoused with battleship Iowa, which had just borne President Roosevelt on the first leg of his journey to the Allied conferences at Cairo and Tehran.

On 23 February, Trippe steamed to Casablanca, where she joined a hunter-killer group built around Card and got underway for the United States.

Late in May, she escorted Hancock on the first leg of the new carrier's shakedown cruise before joining Cooper for electronics countermeasure experiments in Chesapeake Bay.

Between 28 July and 23 October, the destroyer made two round-trip voyages between the United States and southern Italy escorting convoys to and from that bitterly contested campaign.

She spent several weeks in the Hawaiian Islands conducting shore bombardment drills in preparation for duty with the 5th Fleet in the Central Pacific.

Instead, the ship headed west in mid June and escorted convoys between various islands in the Central Pacific, including Iwo Jima, Saipan, Ulithi, and Okinawa.

Her homecoming was brief, however, for on 16 January 1946, she steamed back to Pearl Harbor to prepare for Operation Crossroads, the atomic bomb tests conducted at Bikini Atoll.