During the final months of World War I, O-6 operated out of Philadelphia, Pennsylvania, on coastal patrol against U-boats, cruising from Cape Cod to Key West, Florida. A British merchantman fired six shots at O-6 on 14 July 1918, but caused no appreciable damage. On 2 November, the boat departed Newport in a 20-submarine contingent bound for service in European waters, however, the Armistice with Germany had been signed before the vessels reached the Azores, and they returned to the United States.
After the war, O-6 prolonged her Naval career by operating as a training ship out of New London, Connecticut. Reclassified to a second line submarine on 25 July 1924 while stationed at Coco Solo in the Panama Canal Zone, she reverted to first line class on 6 June 1928 and continued at New London until February 1929, when she steamed to Philadelphia, Pennsylvania, to decommission there on 9 June 1931.
Submarines had proved to be a major weapon in World War I. As U.S. involvement in World War II approached, old submarines were taken out of mothballs and prepared to renew training activities. O-6 recommissioned at Philadelphia on 4 February 1941 and then returned to New London to train students at the Submarine School. On 19 June 1941, O-6 made a trial run to Portsmouth, New Hampshire; the next day O-9 (SS-70) went down 15 nautical miles off Portsmouth. O-6 joined O-10 (SS-71), Triton (SS-201), and other vessels in the search for the lost submarine, but to no avail.
Remaining in the Portsmouth area, O-6 decommissioned there on 11 September 1945, was struck from the Naval Vessel Register the same day, and was sold to John J. Duane Company of Quincy on 4 September 1946. The boat was subsequently scrapped in December 1946.
