Callaghan sailed from the West Coast on 5 February 1944 to plunge into action with the fast-striking Fifth Fleet in smashing air raids on the Palaus, Yap, Ulithi and Woleai from 30 March to 1 April. Based on Manus in April, Callaghan supported the Hollandia operation through important services as picket ship during air strikes, and screening the valuable tankers.
From June to August 1944, Callaghan provided screen for escort carriers softening up, and later supporting the invasions of Saipan, Tinian and Guam. At Saipan, Callaghan’s guns joined in driving off a heavy Japanese air attack on 17 June, helping splash three enemy planes. Fanshaw Bay (CVE 70) was struck by a bomb in this attack, and Callaghan shielded the crippled escort carrier safely back to Eniwetok. Late in August Callaghan began operations as escort for air strikes on the Palaus, Mindanao, Luzon and the Central Philippines in support of the invasion of the Palaus, a stepping stone to the Philippines.
With the long-awaited return to the Philippines scheduled for mid-October 1944, Callaghan steamed in the screen of the carrier force conducting essential preliminary neutralization of Japanese airfields in Formosa and Okinawa. During a heavy enemy air attack on 14 October, she joined in downing several planes. Sailing on to stand guard off the invasion area on Leyte, Callaghan’s force contributed air power in the decisive Battle for Leyte Gulf, which insured the Allied advance in the Philippines against the desperate Japanese efforts to break up the landings.
After pursuing Japanese cripples fleeing north, Callaghan returned to support the Philippine operations, in company with the Third Fleet, for air strikes on Luzon. En route, on 3 November, Reno (CL 96) was torpedoed and Callaghan stood by to protect the stricken cruiser until relief forces arrived, when she was able to rejoin her group for the strikes. Through December, she participated in more air strikes on the Central Philippines and, in January 1945, sailed with the Third Fleet for air raids on Formosa, Luzon, Indo-China, Hong Kong and the Ryukyu Islands.
Through the following months, Callaghan operated at the same active pace, screening carrier strikes pounding Iwo Jima, Okinawa and the Tokyo area. On 18 February, she assisted in sinking a Japanese picket boat and on 3 March, she joined the bombardment of Parece Vela. In late March, she joined a battleship force at Ulithi. From this base, she sailed for the pre-invasion bombardment of Okinawa, where she threw harassing fire ashore during the night of 26 March. This initiated prolonged fire support and screening duty in the dangerous waters off Okinawa during which, in addition to invaluable aid to the troops, Callaghan joined in sinking a Japanese midget submarine and in splashing three dive bombers.
On 9 July 1945, Callaghan took station on the embattled radar picket line, where on 28 July she drove off a biplane intent on suicide with well-directed fire, but the plane, skimming low and undetected, returned to strike Callaghan on the starboard side. It exploded and one of its bombs penetrated the after engine room. The destroyer flooded and fires ignited antiaircraft ammunition, which prevented nearby ships from rendering aid.
Callaghan sank at 0235 on 28 July 1945, with the loss of 47 members of her crew. She earned eight battle stars for World War II service.