Named for Rear Admiral Edward Simpson, a Civil War-era naval hero, the USS Simpson (DD-221) was commissioned on 3 November 1920. From June 1922 through February 1924, the Simpson served with a unit of the U.S. Naval Detachment off Turkey during post-World War I unrest. In 1925, the Simpson joined the Asiatic Fleet and trained at Tsingtao and Chefoo, China. That same year, she was part of a fleet of destroyers dispatched to supplement the Yangtze gunboat patrols. She returned to the United States in April 1932 and underwent an overhaul at Mare Island. On 7 May 1934, the Simpson and the cruiser USS Milwaukee (CL-5) collided during night training exercises off Guantanamo Bay; the Simpson underwent repairs in Philadelphia.
Throughout the summer of 1941, the Simpson escorted two convoys from Argentia to a rendezvous with British warships off Greenland. In September 1941, She was a part of an Iceland-to-Argentia convoy—the first westbound convoy escorted by U.S. warships. When the United States entered the war in December 1941, the Simpson's convoy trips were extended to Britain and she served on transatlantic convoy duty until April 1942, when she received repairs in Boston. During the year following her overhaul, the Simpson escorted convoys, mostly up and down the U.S. East Coast. She traveled to Casablanca in February 1943 and in April 1943 underwent an overhaul in New York.
Returning to duty in May 1943, the Simpson traveled to Curacao, West Indies, and escorted two voyages from Curacao to Northern Ireland. She returned to the United States in October 1943, but within the month she was patrolling off the Azores. On 1 December 1943, the Simpson was designated for conversion to a fast transport (APD-27), but this conversion was canceled, and she continued convoy operations through 1944. She escorted new heavy combatant ships on shakedown and training exercises off the East Coast into 1945.
In the spring of 1945, her armament was replaced with exercise torpedo racks and a winch for handling towed targets; she was reclassified a miscellaneous auxiliary (AG-97) effective 23 May 1945. The Simpson arrived for deactivation at the Philadelphia Navy Yard in May 1946 and was stricken from the Navy list on 19 June. She was sold for scrap to the Northern Metals Company in November 1946.