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 and 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 Batangan, Operation “Double Eagle”. O’Brien returned to her home port 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 and to transit the Columbia River to The Dalles. The destroyer got underway again for the troubled western Pacific 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 in Subic Bay, Philippines, she provided support for air strikes from the 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 forst 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 seven times during this period.
The ship returned to her home port of Long Beach, California, in May 1967. In July she made a second trip to the Dallas, Oregon, 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 returned to the 7th. Fleet operations in the spring of 1968. She put to sea for 7th. Fleet operations on 30 April 1968, arriving in Japan via Pearl Harbor on 29 May. 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 0n 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 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 August, O’Brien escorted carries 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 Somoa, 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 O’Brien 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 carries on Yankee Station before returning to Long Beach on 15 April. Once home, the O’Brien underwent a quick turnaround with a yard period and refresher training preparing the O’Brien for another deployment starting on 6 November. During what proved to be her last deployment, the 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 for repairs. After arrival on the gun line off Vietnam on 13 January 1971, the warship conducted gunnery operations until 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 pulled 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, New Zealand, Pago Pago, American Samoa, and Pearl Harbor.