[1] Following a shakedown cruise to Bermuda in December 1943, Twiggs operated out of Norfolk as a training ship until 12 May 1944, when she departed Hampton Roads in company with the aircraft carrier Franklin and the destroyers Cushing, and Richard P. Leary and proceeded, via the Panama Canal and San Diego, to Hawaii for operations in the Pacific Theater of World War II.

After arriving at Pearl Harbor on 6 June, Twiggs took part in exercises and drills in Hawaiian waters and escorted convoys operating between Oahu and Eniwetok.

In the following days of heavy enemy air activity, she continued to support the invasion and, on one occasion, rescued a downed aviator from the escort carrier Petrof Bay.

Twiggs departed Leyte on 25 October, steamed via Mios Woendi Island to Manus, and arrived at Seeadler Harbor on 1 November.

On 10 December, Twiggs left Kossol Roads, between Peleliu and Angaur, with a task force bound for the occupation of Mindoro Island.

Raids by both torpedo and kamikaze aircraft continued as Twiggs operated northwest of Cape Bolinao in support of the Lingayen assault.

On 16 February, the force arrived off Iwo Jima where Twiggs quickly began fire support for pre-assault underwater demolition operations off the eastern beaches.

On 17 February, a kamikaze plane attack on Twiggs resulted in a close call when the aircraft, in an obvious attempt to crash into the destroyer, crossed her fantail before hitting the water off her port beam and sinking without exploding.

On 28 April, a day of heavy air activity, a kamikaze splashed close to Twiggs while she was on radar picket duty with Task Group 51.

Bomb blast and fragmentation from the splashed airplane blew in the hull plating between the main and first platform deck causing structural damage.

The plane then circled back and completed its kamikaze mission by crashing; the explosion enveloped the destroyer in flame and, within an hour she had sunk, leaving only 188 survivors.