Following shakedown, Wainwright began duty with the Atlantic Fleet in conjunction with the Neutrality Patrol which had been established by President Franklin D. Roosevelt soon after World War II broke out in Europe early in September 1939 to keep hostilities from spreading to the Western Hemisphere.
Just before the opening of hostilities between Japan and the United States, Wainwright embarked upon a mission which indicated an acceleration in America's gradual drift into the Allied camp.
The convoy steamed first to Trinidad in the British West Indies, in order that the "short-legged" destroyers might refuel there before beginning the long South Atlantic leg of the voyage to Cape Town.
The escorting American destroyers headed back to the United States, but this time they put to sea as full-fledged belligerents.
No longer simply trying to prevent the spread of hostilities to the Western Hemisphere, she patrolled instead to protect America's shorelines and seagoing traffic along her coast from Germany's undersea fleet.
That duty continued until mid-March 1942, when the warship received orders to join the British Home Fleet as part of an American force composed of Wasp, North Carolina, Washington, Tuscaloosa, Wichita, and seven other destroyers.
Her most famous and most successful encounter with the enemy came three months after she arrived in European waters while the destroyer was protecting the North Russia convoys.
The force, built around London, Tuscaloosa, Wichita, Norfolk, Wainwright, Rowan, and seven British destroyers, departed Seydisfjord, Iceland, on 1 July.
After that attack, a two-hour lull in the action allowed Wainwright to resume her original mission, refueling, but the enemy returned at about 1820.
Her antiaircraft gunners damaged three or four enemy planes and generally discouraged the raiders from pressing home their attack with the vigor necessary for greater success.
Assembled at Casco Bay, Maine, that group got underway on 24 October and, two days later, rendezvoused with the remainder of Task Force 34 (TF 34), which had sortied from Hampton Roads.
For Wainwright, the Naval Battle of Casablanca opened just before 0700 on 8 November when her antiaircraft gunners joined those of the other ships of the Covering Force in chasing away two Vichy French planes.
Their efforts cost the French dear, four Vichy destroyers and eight submarines were sunk while the light cruiser and two destroyer-leaders suffered severe damage.
In addition to her part in the engagement with the French warships, Wainwright also participated in the intermittent gun duels with batteries ashore.
During her stay in Casablanca after one such voyage, she played host to a group of Moroccan dignitaries including Sidi Mohammed, the Sultan of Morocco.
Two near misses flooded both main engine rooms in Mayrant, and Wainwright joined in escorting the stricken warship into port under tow.
Later, she supported the "leap-frog" amphibious moves employed by Major General George S. Patton in his rampage across northern Sicily to the Strait of Messina.
On 5 September, she resumed convoy duty, this time between North Africa and Sicily, frequently warding off Luftwaffe air raids.
Italy proper had been invaded early in September, and late in October, the warship was called upon to bombard enemy installations around Naples in support of the 5th Army’s advance on that city.
While conducting an antisubmarine sweep 10 miles (16 km) north of Algiers in company with Niblack, Benson, and Calpe, she made contact with U-593.
After returning to Algiers and delivering her prisoners to British authorities there, she resumed convoy and patrol duties in North African waters.
She steamed homeward in company with Ariel (AF-22) and Niblack via Ponta Delgada in the Azores, arrived at New York on 12 February, and entered the navy yard there for a three-week overhaul.
Wainwright arrived in Ominato Ko on 12 September and began a six-week tour of duty in support of the occupation forces.