After shakedown out of Bermuda, British West Indies and Norfolk, Virginia O'Brien joined convoy forces 14 May 1944 en route to Scotland and England.

Following temporary repairs on the Isle of Portland, England, O'Brien escorted a convoy to the Boston Naval Shipyard where she underwent extensive work.

While under continuous air attack, O'Brien crewmen attempted to extinguish oil fires in Ward, caused by Japanese kamikazes, until ordered to sink the stricken transport by gunfire.

After several days of escort duty and shore bombardment during the landing of Army assault troops, she proceeded to Manus Island, for repairs.

The O'Brien was assigned to Task Group 1.7 in support of Operation Crossroads, the first post-war atomic bomb testing, which took place at Bikini Atoll from June through July, 1946.

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 7th Fleet with the cruiser Helena, 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 to 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.

Called to the aid of a surrounded outpost at Thach Ten, Quảng Ngãi Province, the ship's fire helped turn back a North Vietnamese regiment.

After repairs at Subic Bay, Philippines, she provided support for air strikes from Tonkin Gulf while guarding five different carriers in January 1967.

Following an ASW exercise in the Sea of Japan with Japanese warships, the destroyer sailed south for operations in the Gulf of Tonkin, beginning shore bombardment duties upon arrival on 24 June.

After a short port visit to Singapore in early August, the destroyer returned to Japan for a two-week upkeep period alongside tender Hector.

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.

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 USS Ranger for winter exercises in the Sea of Japan.

Once home, the destroyer underwent a quick turnaround, with a yard period and refresher training preparing the warship for another deployment starting on 6 November.

After arrival on the gun line off Vietnam on 13 January 1971, the warship conducted gunnery operations until a 6-foot (1.8 m) crack in her hull forced her into dry dock at Subic Bay on 2 February.