Following shakedown off Guantanamo Bay in September, Sampson tested and evaluated the Tartar Missile System off Puerto Rico. Homeported at Norfolk, she conducted further tests and trials in early 1962 before joining Destroyer Squadron (DesRon) 18 and Destroyer Division (DesDiv) 182 in July. Composed completely of missile ships, DesRon 18 was the most modern squadron in the Navy. Further radar and missile tests followed in 1963 and, in July, Sampson operated in the Midshipman Training Squadron. In January 1964, Sampson fired two Tartar missiles under simulated combat conditions.
In January 1965, Sampson sailed for her first Mediterranean deployment, but an electrical fire on the night of 14 January caused extensive damage to her fire control capability and forced her to abbreviate her deployment and enter the Norfolk Naval Shipyard for repairs on 15 March. The destroyer returned to fleet duties on 24 June. While conducting gunnery exercises on 17 July Sampson spotted a 50-foot sailing sloop, Cecelia Anna, flying distress signals. Sampson rescued the six crewmen and mascot puppy moments before the sloop sank.
In 1966 Sampson conducted gunnery exercises and escort duties near Guantanamo Bay Cuba then, in March, deployed to the Mediterranean for operations with the 6th Fleet. She returned to Norfolk in August. In November, following three weeks of exercises in the Caribbean and additional tests, Sampson got underway to participate in exercise “Lantflex 66”.
Sampson deployed to the Mediterranean in mid-1967. While there, a Sampson radarman rescued a German seaman from the harbor at El Ferrol de Caudillo, Spain. Leaving the 6th Fleet at the end of August 1967, Sampson steamed back to the United States, and soon shifted to her new home port of Charleston.
Sampson operated out of Charleston in the Atlantic and Caribbean during 1968 until again deploying to the Mediterranean in October. She returned to Charleston in January 1969 and resumed operations in the Atlantic and the Caribbean until redeploying to the Mediterranean in October of that year. After six months with the 6th Fleet, she returned to Charleston on 28 March 1970. Sampson operated out of Charleston in the western Atlantic until 23 September, when, after only two days notice, she got underway for special operations in the Mediterranean. She cruised with John F. Kennedy (CVA-67), then with Saratoga (CV-60), during the Levantine crisis.
She ended 1970 and began 1971 in Charleston. On 9 April she performed exercises and type training. She cruised with the 6th Fleet for six months, participating in exercises with both American and NATO forces. By 16 October, the guided missile destroyer was back in port at Charleston. She spent the rest of 1971 preparing for a compressed regular overhaul. From mid-May until 9 July Sampson was underway for post-overhaul trials, exercises, and refresher training before reporting to her new home port, Athens, Greece. She met the Soviet Black Seas fleet at the straits of Bosphurus during the 1973 Israeli/Arab war. The guided missile destroyer remained in the Mediterranean into 1974.
Sampson underwent a major overhaul in the Portsmouth shipyard during 1980–81. In November 1982 Sampson deployed to the Persian Gulf and later the Mediterranean. Sampson was on station off Beirut when the US Embassy was bombed. The ship returned to Mayport, FL in May 1983. From October to December of that year, Sampson was deployed in the eastern Caribbean in support of Operation Urgent Fury.
Sampson was decommissioned on 24 June 1991 exactly 30 years after commissioning, stricken from the Naval Vessel Register on 20 November 1992.