After fitting out at Philadelphia, Berkeley set out for her assigned homeport of Long Beach, California, mooring there on 16 March 1963 after visits to Port Royal, South Carolina; Kingston, Jamaica; and Acapulco, Mexico.

At the end of a short visit to the Rose Festival at Portland, Oregon, in early June, Berkeley entered the San Francisco Naval Shipyard for a three-month availability.

Detached on 18 April, Berkeley proceeded to Hong Kong, where she embarked Vice Admiral Thomas H. Moorer, and sailed on to Bangkok, Thailand, for the annual Southeast Asia Treaty Organization (SEATO) conference.

After rejoining her task group in late April, the guided missile destroyer spent the next two months screening the carriers Kitty Hawk and Ticonderoga and participating in a SEATO landing exercise in the Philippines.

Underway with the carrier Hancock in late November 1965, Berkeley made a brief stop at Subic Bay in the Philippines before proceeding to the South China Sea for combat operations off Vietnam.

This naval air campaign, begun the previous March, sought to cut the flow of munitions and supplies to the Viet Cong insurgents in the south by interdicting North Vietnam's logistics pipelines through Laos and across the demilitarized zone (DMZ).

Assigned to the northern search-and-rescue (SAR) station in the Gulf of Tonkin, Berkeley, in company with the cruiser Topeka and destroyer Brinkley Bass, patrolled the area through the end of January 1966.

In company with the destroyer Arnold J. Isbell, Berkeley coordinated rescue helicopter flights, and those of fighter aircraft from the carriers Ranger and Kitty Hawk, as the two warships closed the ditch site.

At the same time, her combat information team directed friendly air strikes against enemy gun emplacements and coordinated three SH-3 helicopters from Yorktown and England as they retrieved the six survivors from the water.

Over the next three weeks, the warship's crew took part in the annual "Coral Sea Celebration"—which honored the victory won by the Allied navies in May 1942—and visited Sydney, Adelaide, and Hobart in Australia as well as Auckland, New Zealand.

Following the early January 1967 Exercise "Snatch Block," which was devoted to SAR and electronic countermeasure (ECM) procedures, Berkeley spent the next three months preparing for another Far East deployment.

During this period, her engineers and technicians busied themselves maintaining and improving the warship's complex electronic and fire-control systems, a task abetted by a three-week tender availability in early February.

Underway again three days later, Berkeley sailed with the aircraft carrier Constellation to the Gulf of Tonkin before joining the cruiser Saint Paul and TU 77.1.1 for a "Sea Dragon" patrol.

Over the next two months, Berkeley conducted three gunline patrols—firing nightly interdiction missions, searching for waterborne logistics craft, and bombarding supply routes—off both North Vietnam and the Vung Tau Peninsula.

After firing numerous bombardment missions against enemy troops and tanks advancing toward Hue, Berkeley joined Operation Pocket Money, the mining of the river approaches to Haiphong, North Vietnam, on 9 May.

After a five-day visit to Hong Kong in mid-October, Berkeley steamed for home—with brief stops at Subic Bay, Wake Island, Guam, and Pearl Harbor and underway refueling by the auxiliary Ponchatoula—and arrived at Long Beach on 10 November.

The overhaul gave the guided missile destroyer the new tactical data system, a sonar upgrade, new communications and electronic warfare gear, and two new 5-inch gun mounts.

In company with Constellation and the rest of TG 77.6, Berkeley conducted 11 days of operations with Pakistani, Iranian, and British naval units before visiting Karachi, Pakistan, on 19 November.

Following six weeks of contingency operations, Berkeley began her long transit home on 24 January 1980, arriving in San Diego via Subic Bay and Pearl Harbor on 19 February.

The guided missile destroyer then moved back to Subic Bay, after diverting for stops at Sattahip, Thailand, and Hong Kong, where she joined the Kitty Hawk battle group.

Departing on 13 May, the group sailed into the Indian Ocean for six weeks of antiair and surface warfare exercises before putting into Geraldton, Australia, for a week-long port visit in mid-July.

Underway for sea trials on 18 March, the guided-missile destroyer carried out a series of evaluations, local operations, and refresher training over the summer and fall in preparation for her next deployment.

Arriving in the Philippines on 30 January, Berkeley trained on the Tabones gunfire range during February; and, following a 12-day visit to Subic Bay, the guided-missile destroyer steamed to Pusan, South Korea, in early March.

Berkeley arrived in the Arabian Sea on 16 April and served there for the next six weeks, helping to assure Western access to oil and seeking to stem the spread of Soviet influence in the region.

Berkeley spent the next nine months conducting local operations in California waters, the highlight of which was the mid-October surveillance of a Soviet intelligence gathering trawler prowling the missile-test range at San Clemente Island.

Starting with a visit to Cairns from 4 to 8 September, she moved on to stops at Townsville, Mackay, and Gladstone before putting into Sydney on 26 August for a week-long naval celebration with over 60 warships from 16 countries.

Berkeley then made a visit to Bell Bay in Tasmania before rendezvousing with New Jersey on 18 October for the transit home, arriving in San Diego via Pearl Harbor on 9 November.

Passing through the Strait of Malacca in late December, Berkeley and the Enterprise battle group sailed into the Indian Ocean and moored at Diego Garcia Island on 5 January 1990.

Next, the group operated in the northern Arabian Sea and Persian Gulf—keeping an eye on the still-tense ceasefire between Iran and Iraq—until putting into Muscat, Oman, for a port visit on 20 January.

During these missions, which were intended to help interdict drug smuggling, the warship used surface-search radars and other equipment to spot small craft, which were then boarded by Coast Guard detachments.