1921–1930

Afer commissioning, Bainbridge reported to the United States Atlantic Fleet. She operated along the United States East Coast and in the Caribbean with the fleet, carrying out tactical exercises and maneuvers until October 1922. She departed for Constantinople to join the Naval Detachment in Turkish waters. On 16 December 1922 she rescued approximately 500 survivors of the burning French military transport Vinh-Long about 10 nautical miles (19 km; 12 mi) off Constantinople. For extraordinary heroism during the rescue Lieutenant Commander Walter A. Edwards received the Medal of Honor.

In 1923, at Newport, Rhode Island, Bainbridge served temporarily as flagship of Commander, Scouting Fleet. She then joined Squadron 14, Scouting Fleet, in the Atlantic Fleet.

Between 1923 and 1928 Bainbridge participated in annual fleet concentrations, tactical and joint maneuvers, and fleet and destroyer competitions. In 1927 she was assigned temporary duty with the Special Service Squadron for patrol duty off Nicaragua during internal disturbances there. During several summers Bainbridge participated in the training program of the Scouting Fleet, making summer cruises with reservists. On 23 December 1930 she was placed out of commission in reserve at Philadelphia, Pennsylvania.

1932–1937

On 9 March 1932 Bainbridge was placed in reduced commission and attached to Rotating Reserve Division 19, taking part in United States Naval Reserve training cruises. She was placed in full commission on 5 September 1933 and assigned to Destroyer Division 8, Scouting Force. For a short period she served with the Special Service Squadron in the Florida Keys and at Guantanamo Bay Naval Base at Guantánamo Bay, Cuba, and later was assigned to the Pacific, arriving at San Diego, California, on 5 November 1934. While serving on the United States West Coast, Bainbridge made cruises to British Columbia in Canada, the Alaska, and Hawaii. She was placed out of commission in reserve at San Diego on 20 November 1937.

1939–1941

Recommissioned on 26 September 1939 Bainbridge was as signed to Division 62 and operated on the Neutrality Patrol in the Panama Canal Zone until the summer of 1940 when she reported to Key West, Florida, for patrol duty. During the early part of 1941 she cruised along the northeast coast and between May and November 1941 made three convoy escort voyages to Newfoundland and Iceland.

World War II

The United States entered World War II with the Japanese attack on Pearl Harbor on 7 December 1941. Between December 1941 and July 1945 Bainbridge operated as a convoy escort in the waters off the U.S. East and Gulf Coasts and in the Caribbean with the exception of five trans-Atlantic escort crossings to North Africa between February and December 1943.