Prior to 7 December 1941, as flagship of Destroyer Squadron 7, Plunkett operated in the Western Atlantic and in the Gulf-Caribbean area on Neutrality Patrol. Initially in the latter area, she joined other Neutrality Patrol vessels off Tampico to prevent the departure of several German steamers, then cruised off Martinique, French Antilles to prevent the dispatching of warships, equipment, and gold to the Vichy government. Patrol and convoy missions in the North Atlantic followed, and, on 7 December 1941, she was enroute from Reykjavik to Argentia.
Plunkett continued such duty until joining TF 39 on 20 March 1942. Six days later she departed the East Coast for Scapa Flow and arrived in the Orkneys 4 April to commence operations with the British Home Fleet. Employed on North Sea patrols and escort work over the first leg of the Murmansk run, she was relieved, by Mayrant in mid-May and assigned to escort battleship USS New York back to the United States. Coastwise and Caribbean escort duty followed and in August she returned to the North Atlantic to accompany U.K. bound convoys. On 2 November, she departed New York on her first escort run to North Africa. Delayed enroute to allow time for the clearance of wreckage from her port of destination, her group delivered its charges with their reinforcement troops and equipment to Casablanca on the 18th. Then, after patrolling off the Moroccan coast she returned to New York and local operations off southern New England.
Another transatlantic convoy to Casablanca preceded shore bombardment exercises in Chesapeake Bay, after which she escorted coastal convoys until May, 1943. On the 10th she sailed for Oran, Algeria, with TF 60; and, between the end of May and July, she was employed on HUK, ASW, and convoy escort assignments in North African waters.
On 6 July, she cleared Mers-el-Kébir as a unit of the Western Task Force for the invasion of Sicily. During the invasion, she screened the merchant ships and minelayers of TG 80.5, then patrolled off the Gela anchorage and covered minelaying operations. On the 12th, she departed the assault area, returning on the 17th, to Scogletti, and on the 31st, to Palermo, with convoys. During August, she participated in numerous landings on the Sicilian coast and, in September, joined TG 81.6 to screen the transports and landing craft for the assault on the Axis boot at Salerno. Early on the morning of 13 September, she and Mayo aided the bombed and burning British hospital ship, Newfoundland. The crew of the Mayo was sent aboard the hospital ship to fight the fires. The struggle to save the ship continued for over 36 hours, but, in the evening of the 14th, Plunkett, on orders, fired on and sank the hulk.
North Africa-Naples convoys, interspersed with fire support missions, continued until 21 January 1944, when she sailed to escort the follow up assault group to Cape Anzio. After delivering the craft, she remained in the area to screen the transports. On the 24th she fell victim to one of the numerous air attacks which, previously, she had helped to drive off. At 1738, condition red was sounded. A few minutes later the attack was launched with two glider bombs coming in on the port beam, and two Ju.88s closing in from up ahead. Speed was increased; maneuvering was radical. The glider bombs finally dropped, at 200 yards distance, but more planes had joined the foray to commence a sustained 17-minute battle. It ended at 1757 as Plunkett took a 250 kg. bomb and caught fire. The bomb killed 23, left 28 missing, with as many, and more, wounded, and caused extensive damage to her fire control apparatus, armament, and port engine. By 1821, all fires were out and the destroyer proceeded, on one engine, to Palermo. Temporary repairs enabled her to reach Casablanca and, finally, New York, where repairs were completed.
On 5 May 1944, she again departed New York for European waters. Arriving at Belfast on the 14th, she remained until 3 June, then sailed toward the English Channel to join the armada staging for the invasion of France. On 6 June, she screened the transports off Omaha beach. Fire support and patrol duties followed until the 9th, when she sailed back to England. Returning to the French coast a few days later, she added shore bombardment to her duties.
In July, Plunkett returned to the Mediterranean to prepare for another assault landing, and on 13 August, she sailed from Naples to support operation “Dragoon,” the invasion of southern France. During that operation she carried officials to and from the beaches in addition to performing her screening duties. She next added fire support and shore bombardment off St. Tropez, Port de Boue, and Marseilles to her mission, and continued those duties, particularly on the Italian-French border, until 23 November. She then sailed for Oran, whence she escorted a convoy back to the United States, arriving at New York, 16 January 1945.
Plunkett engaged in training exercises, ASW patrols, and experimental testing until early May, when she resumed transatlantic escort work. The war in Europe ended before she reached the U.K., but hostilities in the Pacific still raged. On 27 May she returned to the East Coast, underwent extensive alterations and refresher training, and got underway for the Pacific 6 August. She transited the Panama Canal 13 August and was enroute to San Diego the day the war ended. In September, she escorted occupation forces from the U.S. to Japan; then, in October and November, assisted in ferrying more from the Philippines. Later in November, she sailed northeast to the Aleutians, where she operated until ordered back to the East Coast for inactivation.
Plunkett decommissioned 3 May 1946 and was berthed at Charleston as a unit of the Atlantic Reserve Fleet. She remained there until reactivated and transferred, under the loan provisions of the Military Assistance Program, to the Nationalist Chinese government, 16 February 1959. Renamed Nan Yang (DD-17), she remains with that country's navy into 1970.