Du Pont sailed from Newport 6 May 1919 to patrol off the Azores during the historic first transatlantic airplane flight, made by Navy seaplanes, then visited Brest, France, before returning to New York 15 June. She sailed 10 July for the Mediterranean and on the 27th reported to commander, US Naval Forces, European Waters, at Constantinople, Turkey. She carried mail and passengers in connection with relief in eastern Europe, and investigated conditions in Lebanon, Syria Egypt, and Greece. Returning to New York 21 July 1920, she was placed in reserve and operated with 50 percent of her complement in training duty along the Atlantic coast until placed out of commission at Philadelphia 19 April 1922.

Recommissioned 1 May 1930 Du Pont operated along the east coast and in the Caribbean, in practice and exercises and on reserve training cruises. Between 13 and 29 March 1931 she escorted Arizona (BB-39) with President H. C. Hoover embarked for visits to Ponce, P.R., and St. Thomas, V.I., then returned to tactical exercises with the fleet and occasional duty as a plane guard.

Between 9 January and 22 October 1932, Du Pont cruised to the west coast, returning to Norfolk to join Rotating Reserve Squadron 19. She operated from Boston training Naval Reservists until assigned temporary duty on patrol off Cuba from September 1933 until February 1934.

On 15 August 1934 Du Pont returned to active commission. She left Charleston, SC, 15 September, served as target vessel and plane guard in the Caribbean, then arrived at San Diego 9 November. Based there she served in training and tactical development with the fleet cruising to Alaskan waters and Pearl Harbor on a problem during 29 April-10 June 1935. She sailed from the west coast 27 April 1936 for the annual fleet problem held that year in the Canal Zone, then transited the Canal and arrived at Jacksonville, FL, 7 June for Naval Reserve training duty along the east coast. Arriving at Philadelphia Navy Yard 29 September 1936, Du Pont was placed out of commission 14 January 1937.

With the outbreak of war in Europe Du Pont was recommissioned 16 October 1939 for duty on the Neutrality Patrol. She patrolled along the east coast, trained reservists, and spent several periods training with submarines out of New London. Between 7 July 1941 and 26 February 1942 she escorted five vital convoys to Argentia, Newfoundland and Iceland, continuing escort and antisubmarine patrol duty in the Atlantic as far north as Argentia and south to the Caribbean. Du Pont, 16 March 1942, rescued 30 survivors from a torpedoed merchantman. From 8 May 1942 to 19 January 1943 she guarded convoys from New York and Norfolk to Key West and Guantánamo Bay.

After overhaul Du Pont returned to the Caribbean to escort tanker convoys between Aruba, Netherlands West Indies and Guantánamo Bay until 17 May 1943 when she sailed from Aruba to the Mediterranean. She arrived at Algiers, Algeria, 1 June, and put into Casablanca 6 days later. The destroyer sailed on 9 June for New York in the escort for Card (CVE-11), rescuing four men from downed aircraft during hunter killer operations enroute. She arrived at New York 6 July.

Between 17 July and 12 September 1943 Du Pont made two voyages to the United Kingdom on convoy escort duty. On 25 September she sailed from Norfolk for an antisubmarine patrol with a hunter-killer group centered on Card. On 6 October she joined the screen for Bogue (CVE-9) during exercises in Casco Bay and Long Island Sound. The group sailed from Norfolk 14 November to give close support to a Gibraltar-bound convoy. On the return passage one of Bogue’s planes sighted and bombed a surfaced German submarine, U-178, 12 December. Du Pont and George E. Badger (DD-196) continued the attack driving the submarine to the surface on the morning of the following day. The destroyers opened fire and after the submarine's conning tower exploded, rescued 46 survivors including the captain as U-173 sank in 26 degrees 19’ N, 29 degrees 58’ W. Du Pont shared in the Presidential Unit Citation awarded the Bogue task group for distinguished success in operations against submarines.

Du Pont escorted a convoy to Gibraltar and back to Boston between 25 January and 9 March 1944, then returned to escort duty in the Caribbean. She left Norfolk 11 June in the screen of Albemarle (AV-6) sailing by way of Casablanca to Avonmouth, England, arriving 28 June. Du Pont returned to Boston 13 July with Albemarle who was carrying casualties from the Normandy invasion.

After overhaul and refresher training, Du Pont put into Charleston Navy Yard 16 September 1944 to undergo conversion to an auxiliary vessel. Reclassified AG-80, 26 September 1944, she sailed from Charleston 9 October and arrived at Key West 2 days later to act as target ship for Fleet Air Wing 5. She rescued two downed aviators 24 November and 2 days later, transferred her doctor to a Norwegian merchantman to render emergency treatment. She continued to serve off Florida aiding aviation training until 1 April 1946 when she arrived at Boston. Du Pont was decommissioned 2 May 1946 and sold 12 March 1947.

In addition to the Presidential Unit Citation awarded to TG 21.13, Du Pont received three battle stars for World War II service.