After fitting out at Boston, R-6 reported to Submarine Division 9 (SubDiv 9) of the United States Atlantic Fleet at New London, Connecticut, on 16 September 1919.

R-6 got underway on 4 December 1919 for Norfolk, Virginia, and winter exercises with her division in the Gulf of Mexico from 21 January to 14 April 1920.

R-6 was transferred on 16 July 1923 to Hawaii, where she remained for the next seven-and-a-half years engaged in training and operations with fleet units.

R-6 was recalled to the Atlantic on 12 December 1930, transited the Panama Canal on 18 January 1931, and arrived on 9 February 1931 at Philadelphia, Pennsylvania, where she 'decommissioned on 4 May 1931.

Upon recommissioning at New London on 15 November 1940, R-6 was assigned to SubDiv 42 and departed on 10 December 1941 for the submarine base at Coco Solo, Panama Canal Zone, where she remained until 16 June 1941.

She was transferred to SubDiv 31 at Saint Thomas, United States Virgin Islands, on 22 June 1941 and operated from there until returning to New London on 8 October 1941 for a refit.