Following a shakedown cruise which took the ship to Guantanamo Bay, Cuba, Wiltsie transited the Panama Canal on 8 July 1946 and proceeded to San Diego, California.

She subsequently operated out of Qingdao, China, on exercises and maneuvers while standing by the American community in that port during rising local tensions between the communist and Nationalist Chinese.

Returning to San Diego on 31 August, the destroyer soon sailed for Hawaii, where she participated in Operation "Miki", a mock invasion of the Hawaiian Islands in which Army, Navy, and Air Force units all took part.

Returning to the west coast soon afterwards, Wiltsie spent the period from December 1949 to April 1950 at the Mare Island Naval Shipyard, Vallejo, California, undergoing an overhaul.

Wiltsie returned to San Diego in March 1951, underwent repairs at Long Beach, California and subsequently departed the west coast for her fourth tour of duty in the Far East.

While preparing to abandon the Wonsan siege in accordance with the armistice stipulations, Wiltsie screened minesweeping operations and joined in the last-minute shelling of enemy ground targets.

Later in the month, she participated in exercises in support of Marine Corps units engaged in night reconnaissance and in amphibious and paratroop landing training at San Clemente Island and at Camp Del Mar, California.

Drydocked during August and September for hull and sonar dome repair, Wiltsie put to sea soon afterwards for tests and trials of her DASH (drone antisubmarine helicopter) qualification system which ended successfully on 3 November.

The destroyer subsequently participated in Operation "Union Square", an extensive fleet exercise, before returning to San Diego to prepare for the ship's 14th WestPac deployment.

Wiltsie was diverted to duty with Coral Sea and USS Hancock during bombing raids on Viet Cong (VC) positions in South Vietnam in February.

While at Guam for a refueling stop, the destroyer suffered slight damage on 22 June when a fuel barge collided with the ship, necessitating repairs which delayed her for 15 hours.

After a brief period of upkeep, Wiltsie proceeded to the northern search and rescue (SAR) station, approximately 50 miles (80 km) east of the North Vietnamese port of Haiphong, to stand by with Towers ready to recover downed airmen.

The heavy seas battered open a seam forward in Wiltsie; caused three cracks in the fantail area of the main deck and the loss of two ladders; and ripped two holes in the port bow of the motor whaleboat.

After rest and relaxation at Hong Kong, an upkeep alongside USS Klondike, and an in-port period at Subic Bay, Wiltsie returned to the SAR station in Tonkin Gulf, operating in company with King.

Two Oriskany planes went down on 10 January 1968; Wiltsie provided communications relays where necessary and closely plotted aircraft positions, while King assumed air control function and direction.

Wiltsie's SAR tour was largely uneventful, as monsoon activity curtailed American air strikes over the north, and no opportunities presented themselves to pick up airmen.

Departing there on 22 February in company with Buck and King, Wiltsie made a fuel stop at Darwin and visited Brisbane from 2 to 7 March before proceeding on to the west coast of the United States.

Underway again soon afterwards, bound for the ship's WestPac deployment, Wiltsie refueled at Midway, steamed on picket station ahead of Oriskany, and arrived at Subic Bay on 10 May.

On that day, Wiltsie participated in sinking the after section of the hull of USS Frank E. Evans, the destroyer that had been cut in two during a collision with Australian aircraft carrier HMAS Melbourne the previous 3 June.

Two days later, with ComDesDiv 72 embarked, Wiltsie got underway with the remainder of her division to escort Bonhomme Richard back to the United States and arrived at San Diego at the end of a fortnight's voyage.

Departing Luzon on 18 September, Wiltsie sailed for South Vietnam to perform 22 days of gunfire support duty to assist operations of the United States 1st Air Cavalry Division; the 1st Australian Task Force; and an ARVN battalion.

Arriving at her station in the Gulf of Thailand on the morning of 23 October, Wiltsie supported the ARVN 21st Division with gunfire, shelling communist troop concentrations, gun positions, and supply lines for five days, expending 485 rounds of 5-inch projectiles.

Wiltsie reduced speed to 12 knots (22 km/h) in the worsening weather conditions before putting into Buckner Bay, Okinawa, to refuel on 2 November before again setting out for Sasebo.

Wiltsie, joined by Richard B. Anderson and the Japanese Maritime Self Defense Force vessels Asagunmo, Makiguma, and Hic-kugo, conducted a day-long search for her missing sailor but came away empty-handed.

In March and April, she served plane guard duty for Oriskany and USS Enterprise; and, in June, entered the Long Beach Naval Shipyard for an overhaul which lasted until mid-November 1971.

While in the Hunters Point Naval Shipyard preparing for its new role, however, Wiltsie received word on 22 May that—instead of beginning reserve duty in July she would head back to the Far East for its 19th deployment in the western Pacific.

Typhoon Elsie, which was approaching near the DMZ, temporarily suspended Wiltsie's gunfire support operations while she avoided the tropical disturbance by moving to safer waters.

Returning to Subic Bay for upkeep the next day, the destroyer remained in port until 27 September when it sailed for the Gulf of Thailand for gunnery support duties off the west coast of Vietnam.

In the predawn hours of 28 November, an A-6 Intruder aircraft crashed upon takeoff; and Wiltsie proceeded to the scene of the accident, pinpointing the location and vectoring rescue helicopters from Saratoga to the point.

Arriving at Yokosuka, via Adak, Alaska, on 28 June, the destroyer shifted to Kure before conducting ASWEX 7–73 with Japanese Maritime Self Defense Force units from 9 to 12 July.