On 3 September 1965, she successfully fired two improved Tartar missiles off Okinawa. After a 1-day stop at Sasebo, "Joseph Strauss" proceeded south in the screen of . Upon arrival in the South China Sea, she was detached for picket patrol in the Gulf of Tonkin during the last three weeks of September She spent the first two weeks of October supporting operations off Vietnam in the screen of "Bon Homme Richard" and . She then returned to Subic Bay for naval gunfire support training which continued off Da Nang, South Vietnam. On 28 October 1965, she , expending 217 5-inch shells in support of a combined ARVN-Marine Corps search-and-destroy operation against the Viet Cong. "Joseph Strauss" thus became the first U.S. Navy guided missile destroyer to fire her guns at enemy targets. As a result of this action, the ship's crew received a commendation from the Commanding General, 2nd U.S. Marine Division. Throughout November she formed an advanced SAR/AAW picket team with in the Gulf of Tonkin. She returned to Yokosuka on 7 December 1965 for upkeep and preparations to resume operations off South Vietnam. "Joseph Strauss" returned to the Gulf of Tonkin 10 February 1966 and remained active in the war zone until heading for Hong Kong exactly one month later. Back in the fighting 26 April, she remained in the war zone until returning to Yokosuka 15 June. That day her home port was changed to Pearl Harbor which she reached 26 July.