After shakedown in Chesapeake Bay, Nantahala departed Norfolk on 22 July for the Dutch West Indies where, after loading a cargo of oil and gasoline at Aruba, she steamed for fleet tanker duty in the Pacific.

While anchored in Ulithi Lagoon, she took part in rescue operations following an enemy midget submarine attack which resulted in the torpedoing and burning of USS Mississinewa (AO-59) on 20 November.

During refueling operations in mid-December, she survived the great typhoon of 17–18 December, although winds, which she recorded at 124 knots (230 km/h), and giant seas caused considerable topside damage.

After returning to Ulithi via Leyte Gulf 21 January, Nantahala next made two refueling deployments from 8 February to 10 March in support of the invasion and capture of Iwo Jima.

Thence, between 22 March and 31 May she took part in three replenishment missions to the Ryukyus where she helped maintain the mobility and striking power of American ships during the invasion and conquest of Okinawa.

Assigned to the main replenishment group, she refueled carriers and escorts of TF 38 during the closing weeks of the war, a period in which the American fleet attacked targets in the Japanese home islands from Hokkaido to the Inland Sea with intensive and devastating naval and aerial bombardments.

On 20 November 1961 Nantahala departed Norfolk for the Dominican Republic where she supported U.S. ships called in to protect the stability of that Caribbean nation's government from possible overthrow by followers of the late dictator Rafael Leónidas Trujillo.

While serving out of Guantanamo Bay in mid-February 1963, she took part in the search for and tracking of Anzoategui, a Venezuelan freighter which was seized by Cuban-oriented leftists off Santo Domingo.

In May Nantahala again replenished ships of the recovery force waiting to pick up Project Mercury Astronaut Commander M. Scott Carpenter, USN, after his orbital flight on 24 May.