Following shakedown in European waters in October and November, Sampson returned to Boston, Massachusetts where she was assigned to the Battle Force of the United States Fleet.

She then cruised through the Caribbean Sea, from 14 November to 15 December, transporting a government mission which was compiling an economic survey of the British West Indies.

Sampson then continued operations out of Norfolk, engaged in Neutrality Patrol along the eastern seaboard to various ports of the Caribbean Sea, steaming as far north as Placentia Bay, Newfoundland.

With the Japanese attack on Pearl Harbor and the subsequent United States declaration of war, Sampson patrolled, with Warrington (DD-383), off Newport, Rhode Island from 23 December 1941 to 12 January 1942 when the two destroyers set course for the Panama Canal Zone.

Sampson spent the next year in a series of coastal patrol sweeps from Balboa to waters off South America, making calls at such ports as Guayaquil, Ecuador; Valparaiso, Chile; and Callao, Peru.

Sampson returned from her last cruise along the South American coast to Balboa, on 7 May 1943 and cleared port on 23 May as one of the escorts for a troopship convoy which reached Noumea, New Caledonia, on 13 June.

On the night of 2 and 3 October, while escorting a convoy from Nouméa to Espiritu Santo, she fired at an enemy submarine and after the vessel submerged, dropped depth charges.

On 11 April, she received the armed guard crew from the merchant ship, Titan, stranded on Cook Reef and transferred them to Celtic in Port Havannah, Efate, New Hebrides.

Three days later, she sailed as the escort for troopship, General Tasker H. Bliss,[citation needed] and arrived at the New York Navy Yard on 4 July.

She returned to New York, guarding a westward convoy, on 8 September 1944 and made four subsequent round trips to the Mediterranean, finally arriving at Boston on 19 May 1945.

She again sailed from Norfolk on 19 August for training operations out of Guantanamo Bay and returned from this cruise to the Philadelphia Naval Shipyard on 16 September for inactivation overhaul.