After a shakedown cruise in the eastern Atlantic, Nicholson escorted convoys through the U-boat-infested, storm-tossed North Atlantic, first from Boston to Iceland and then to Scotland and England until fall 1942. In a brief training period off the Virginia coast, she prepared for the Casablanca invasion but a turbine casualty prevented her participation in the initial landings. She arrived four days later, 12 November, to assist in the consolidation of the beachhead and to patrol.
In 1943, Nicholson took part in the Bizerte campaign and the initial assaults on Salerno, coming under heavy air attack from the Luftwaffe at both Bizerte and Salerno. After five months in the Mediterranean, she returned to the United States for overhaul in preparation for Pacific deployment.
In January 1944, Nicholson sailed from New York. When she reached New Guinea in February, she was assigned to escort LSTs in the Cape Gloucester campaign, already under way.
Throughout the long New Guinea campaign, a matter of successive assaults on coastal points and nearby islands, Nicholson gave gunfire support to troops ashore. She had similar duty in the Admiralties where, during the conquest of Seeadler Harbor, she was assigned to draw fire from an enemy battery on Hauwei. There, a 4-inch shell struck in No. 2 ammunition handling room, killing 3 and wounding 4. Nicholson wiped out the enemy position.
In August 1944 Nicholson joined the Third Fleet in the Marshall Islands. She screened fast carriers in raids on the Bonins, Formosa and the Philippines and supported the invasion of the Palaus and the neutralization of Yap. Returning to the Philippines, her group assisted the Seventh Fleet during the invasion of Leyte and the decisive Battle for Leyte Gulf, from which Nicholson sailed for a Seattle overhaul.
Returning to the western Pacific in February 1945, Nicholson escorted convoys between Guam and Ulithi. In late March, she sailed as part of the Okinawa invasion fleet. On the exposed radar picket line, Nicholson came through untouched by kamikazes and rescued survivors from Little and Morrison when those destroyers were sunk.
Rejoining the Third Fleet for the final air operations against the Japanese home islands, Nicholson was off Honshu at the war’s end. She entered Sagami Wan on 9 August and Tokyo Bay on 15 September. Returning to San Diego on 6 November, she sailed for Panama and Charleston, South Carolina, where she arrived on 23 November to join the Atlantic Reserve Fleet.
Nicholson decommissioned on 26 February 1946, was assigned as a Naval Reserve Training ship in the Third Naval District on 30 November 1948 and recommissioned on 17 July 1950. On 15 January 1951, she decommissioned once more and transferred to the Italian Navy as Aviere. In 1970, she was converted to an experimental gun ship before being stricken and sunk as a target in 1975.
Nicholson earned 11 battle stars for World War II service.