After shakedown out of Bermuda, B.W.I. and Norfolk, Virginia, O’Brien joined convoy forces 14 May 1944 enroute to Scotland and England. Following patrol and escort duty near England, she participated in shore bombardment of Cherbourg, and the invasion of Normandy. On 25 June while supporting minesweeps well inshore of Texas (BB 35), which was engaging German shore batteries at Cape Levi, near Cherbourg, O’Brien’s own gunfire was so accurate that enemy gunnery positions shifted from Texas to O’Brien. She received a direct hit just abaft the bridge, but was able to stay on station long enough to lay a smoke screen for Texas. Thirteen men were killed and nineteen wounded. Following temporary repairs in Portland, England, O’Brien escorted a convoy to the Boston Naval Shipyard where she underwent extensive work.

After training in the Boston and Norfolk areas, she escorted Ticonderoga (CV 14) to the Pacific via the Panama Canal and San Diego for carrier operations with the 3d Fleet east of the Philippines. In early December, she joined Seventh Fleet assault forces at Ormoc Bay, P.I. While under continuous air attack, O’Brien crewmen attempted to extinguish oil fires in Ward (APD 16) caused by Japanese suicide planes until ordered to sink the stricken transport by gunfire. O’Brien’s commanding officer, Comdr. W. W. Outerbridge, had been in command of Ward when she had sunk a Japanese submarine off Pearl Harbor on 7 December 1941. On 15 December 1944, O’Brien fought fires in LST-472 caused by suicide planes, and rescued 198 survivors.

Following a brief patrol period at Mindoro Strait she proceeded to Lingayen Gulf for the invasion of Luzon. On 6 January 1945, a Japanese aircraft crashed into the port side of her fantail causing slight damage. After several days of escort duty and shore bombardment during the landing of Army assault troops, she proceeded to Manus Island, Admiralties, for repairs. She joined fleet carrier forces 10 February 1945 for air strikes against Tokyo, Iwo Jima, and the Bonin Islands. Aircraft attacked her off Kerama Retto 27 March while U.S. forces secured an advance logistics base for the attack on the Japanese home islands. One plane crashed into the water as a result of gunfire while another, a “Val” suicide plane carrying a 500-lb. bomb, crashed into the port side amidships exploding a magazine. Fifty were killed or missing and seventy-six wounded in the valiant crew.

During the summer, the ship underwent repairs at Mare Island Naval Shipyard and training in San Diego. As the war ended in mid-August 1945, she returned to the Third Fleet for patrol duty in Japanese water. O’Brien operated in the eastern Pacific, Hawaii, the Marianas, and Australia through the first half of 1947. She returned to the west coast in the summer and decommissioned at San Diego, California on 4 October 1947.

Three years later she recommissioned at San Diego on 5 October 1950, Commander C. W. Nimitz, Jr. in command, and became the flagship of Destroyer Division 132.

During the Korean War she first joined the TF 77 carrier group in early March 1951. Later that month she joined TF 95. the United Nations Blockading and Escort Force, and participated in the siege of Songin. On 17 July 1951, at Wonsan harbor, shore batteries opened on O’Brien, Blue (DD 744) and Cunningham (DD 752) from three sides in a futile attempt to drive UN vessels from the harbor. The ships went at once into the “War Dance,” an evasive maneuver in which ships steamed in an ellipse at 22 knots firing on batteries in each sector as their guns came to bear. This four and a half hour engagement became known as the “Battle of the Buzz-saw.”

In July and August O’Brien provided covering fire for LSMR bombardment, and coordinated rescue operations which saved three downed Navy pilots and one Air Force pilot. Although both Radio Moscow and Radio Peking reported O’Brien sunk by the North Korean Peoples Army, she returned to San Diego for repairs in late September 1951. On 23 July 1952, she returned to Korea as part of TF 95 and participated in shore bombardment, interdiction and patrol duties near Wonsan Harbor. Ordered to the Seventh Fleet with Helena (CA 75), she provided search and rescue protection for carrier aircraft and shore bombardment fire on the east coast of Korea in September. The ship joined Operation “Feint,” a mock invasion of Kojo from 12–16 October 1952, in which UN forces attempted to lure the enemy into the open. At the end of the month, she left the Korean area for exercises and repairs in Japan before returning to San Diego in mid January 1953.

From the end of the Korean action through 1960, O’Brien made annual operational cruises to the western Pacific. In late January and early February 1955, she operated with Wasp when the Seventh Fleet discouraged Communist resistance to the Nationalist Chinese evacuation of the Tachen Islands off the Chinese mainland.

February to October 1961 was spent in Mare Island Naval Shipyard, Vallejo, California for FRAM II conversion. The ship now specialized in antisubmarine warfare procedures and periodically deployed to the western Pacific. In May 1965, operating with Antisubmarine Warfare Group 1, she was one of the first ships successfully to refuel a helicopter inflight. In June O’Brien successfully refueled a helicopter from Hornet off San Francisco while it made a pioneer non-stop helicopter flight from Seattle, Washington to Imperial Beach, California.

The ship sailed for Seventh Fleet duty in August and was assigned to Taiwan patrol. On 14 November 1965, while patrolling the Taiwan Straits, the ship was ordered to the aid of a Chinese Nationalist patrol craft under attack by Communist torpedo boats. Arriving after the vessel had sunk, she rescued all fifteen survivors, and was praised by Commander in Chief, Nationalist Chinese Navy.

A week later 22 November 1965, more than 600 miles from the rescue, O’Brien saw her first action in the Vietnam War. Called to the aid of a surrounded outpost at Thach Ten, Quang Ngai province, the ship’s accurate fire helped turn back a North Vietnamese regiment. In January arid early February 1966, she supported carrier operations, conducted search and rescue missions in the Tonkin Gulf, and provided gunfire support for the amphibious landing near Cape Batangan, Operation “Double Eagle.”

O’Brien returned to her homeport March 1966 and operated on the West Coast for the next eight months. During a port visit to The Dalles, Oregon, in July O’Brien became the largest vessel to use the locks at the Bonneville Dam arid to transit the Columbia River to The Dalles.

The destroyer got underway again for the western Pacific on 5 November 1966. Following antisubmarine warfare exercises in Hawaii and the eastern South China Sea, O’Brien became flagship for Operation “Sea Dragon,” the surface action task unit off North Vietnam. With Maddox (DD 731), she was ordered to interdict enemy coastal traffic. More than twenty vessels carrying enemy war supplies to the Viet Cong were sunk or damaged by O’Brien. On 23 December 1966, the ship received three direct hits from coastal batteries north of Dong Hoi. Two crewmen were killed and four wounded. After repairs at Subic Bay, Philippine Islands, she provided support for air strikes from Tonkin Gulf while guarding five different carriers in January 1967. In February and March, she was assigned to Taiwan patrol. The ship returned to the Tonkin Gulf in late March first as a carrier escort and then on “Sea Dragon” operations. Again as flagship for Commander, Destroyer Division 232, she was instrumental in significantly slowing coastal supply traffic. She was taken under fire by shore batteries six times during this period.

The ship returned to her homeport of Long Beach, California, in May 1967. In July 1967 she made a second trip to The Dalles before entering Long Beach Naval Shipyard for overhaul. Following refresher training at San Diego, she was assigned to destroyer squadron 29 on 1 February 1968.

She put to sea for Seventh Fleet operations on 30 April, arriving in Japan via Pearl Harbor on 29 May. Following an ASW exercise with Japanese warships, the destroyer sailed south for operations in the Gulf of Tonkin, beginning shore bombardment duties upon arrival on 24 June. Over the next four weeks, O’Brien supported U.S. Army and Marine operations, engaging enemy forces ashore with 5-inch gunfire. After a short port visit to Singapore in early August, the destroyer returned to Japan for a two-week upkeep period alongside tender Hector (AR 7). Returning to the Gulf of Tonkin in late August, O’Brien escorted carriers at Yankee Station for the next month. On one evening, the destroyer was alerted by America (CVA 66) that two men had fallen overboard. The destroyer quickly retraced the carrier’s path and rescued one sailor who had stayed afloat for over five hours. After another naval gunfire support period off South Vietnam in mid-October, O’Brien turned for home. She arrived in Long Beach on 28 November after a long southern cruise that took her to Subic Bay, Philippines; Brisbane, Australia; Pago Pago, American Samoa; and Pearl Harbor.

Following a post-deployment stand down, O’Brien conducted local training operations out of Long Beach through the summer of 1969, the highlight of which was a major warfare exercise off Hawaii in mid-March. After pre-deployment exercises in July and August, the destroyer got underway for the Far East on 8 October.

Like her previous deployment, O’Brien primarily served in Vietnamese waters, conducting carrier escort duties at Yankee Station and naval gunfire support operations through the end of the year. In January 1970, however, the destroyer steamed north to Okinawa, there joining a task group built around Ranger (CVA 61) for winter exercises in the Sea of Japan. Returning to Vietnam in February, the warship spent the next two months supporting the carriers on Yankee Station before returning to Long Beach on 15 April. One home, The destroyer underwent a quick turnaround, with a yard period and refresher training preparing the warship for another deployment starting on 6 November.

During what proved to be her last deployment, O’Brien was plagued by material and equipment problems. Before departing Pearl Harbor for Japan, for example, the destroyer suffered an evaporator failure that required a week of repairs. After arrival on the gun line off Vietnam on 13 January 1971, the warship conducted gunnery operations until a six-foot crack in her hull forced her into dry dock at Subic Bay on 2 February. Following those repairs, O’Brien commenced a seven-week period at Yankee Station and on search and rescue duty. She put in at Subic Bay for repairs again on 17 April and sailed for home at the end of the month, arriving home on 29 May after stops at Manus Island; Brisbane, Australia; Auckland, New Zealand; Pago Pago, American Samoa; and Pearl Harbor.

O’Brien decommissioned at Long Beach on 18 February 1972 and was struck from the Navy list that same day. Tapped for use in a live-fire exercise, the hulk was towed out to sea by tug Sioux (ATF 75) and sunk as a target on 13 July 1972.

O’Brien (DD 725) received six battle stars for World War II service, five battle stars for Korean Conflict service, and three battle stars for Vietnam service (1967).