Wilkes spent the winter preceding America's entry into World War I outfitting—first in the Philadelphia Navy Yard and later in the Torpedo Station located at Newport, R.I.—and conducting fleet maneuvers in Cuban waters.

She returned from those operations at the height of the crisis over the German declaration of unrestricted submarine warfare, arriving in Norfolk on 7 March 1917.

She escorted her charges into Saint Nazaire on 26 June then headed for Portsmouth, England, where she celebrated Independence Day.

Though it appears that she never saw combat with German U-boats, she did witness the results of their depredations once when she rescued 23 survivors of the torpedoed British merchantman SS Purley on 25 July 1917.

Wilkes served as a picket on that second leg of the flight as the fourth ship in a line of 14 destroyers between the Azores and the European continent.

Late each fall, she headed south to participate in fleet maneuvers in Cuban waters, the Caribbean, and the Gulf of Mexico.

During that time, she was based at three different ports—Newport, R.I.; New York, N.Y.; and Charleston, S.C. On 12 April 1922, Wilkes entered the Philadelphia Navy Yard where she was placed out of commission on 5 June 1922.

In the summer of 1926, she was turned over to the Coast Guard, desperately in need of additional ships to suppress smuggling of alcoholic beverages in response to their Prohibition in the United States.