Serving in California during the Mexican–American War on USS Portsmouth, he was a volunteer in the expedition to rescue General Philip Kearny's command, and spent five days en route from San Francisco to Monterey in a small boat carrying despatches.

Following shakedown training in the Gulf of Mexico and Caribbean, Harrison escorted a merchant ship to the Panama Canal Zone, and sailed for New York.

Departing with carrier USS Lexington (CV-16) from Norfolk, Virginia 22 July, the ship arrived Pearl Harbor 9 August and spent the next days training for the important amphibious operations which were to come.

Her job was to screen the carriers as their aircraft softened up Japanese-held islands, and the task group got underway 22 August for strikes against Marcus, Wake, and Tarawa, interspersed with short resupply stops at Pearl Harbor.

With these vital preliminary operations complete, Harrison departed 21 October for duty in the Solomons, long the scene of bitter fighting both on land and sea.

As the Marines landed on Kwajalein and advanced over the numerous islands in the atoll, Harrison entered the lagoon 4 February and rendered close fire support.

Carriers screened by the destroyer and her sisters bombarded enemy airfields and supported the successful landing, after which Harrison arrived Port Purvis on Florida Island in the Solomons on 11 May for a month of local exercises and patrols.

This operation not only constituted a break in Japan's inner ring of defenses, but dealt a death blow to the Empire's naval air arm at the Battle of the Philippine Sea.

After helping to establish this important air base, the destroyer joined a larger task force at Humboldt Bay and departed 13 October for one of the largest operations of the war, the invasion of the Philippines.

Observing the strictest secrecy to insure success, the carriers and their escorts arrived off Japan 16 February and launched a devastating series of strikes against the Tokyo area.

After these attacks, the vast force moved south to support the Iwo Jima landings, scheduled for the 19th, and remained east of the island until returning for another raid on Tokyo 25 February.

Refueling at sea in a remarkable demonstration of the mobility and striking power of carrier forces, the ships then sailed to Okinawa for photo-reconnaissance missions 1 March.

In heavy strikes 18–19 March the carrier forces inflicted great damage on Okinawa in preparation for the invasion, and Harrison shot down another attacking enemy aircraft.

In addition, Harrison with four cruisers and five other destroyers made an anti-shipping sweep along the northern coast of Honshū; but, testifying to the thoroughness of American surface and submarine attrition, gained not one contact.

Then during the night of 30–31 July Harrison and the rest of her squadron swept Suruga Wan, near Tokyo, and in the very shadow of Mount Fuji bombarded railroad yards and an aluminum plant.