The fort remained in Federal hands throughout the Civil War. With the end of hostilities in 1865, the fort’s population had declined to 1,013, consisting of 486 soldiers or civilians and 527 prisoners. The great majority of prisoners at Fort Jefferson were Army privates whose most common transgression was desertion. The most common transgression of civilian prisoners was robbery.
By 1888, the military usefulness of Fort Jefferson had waned, and the cost of maintaining the fort due to the effects of frequent hurricanes and the corrosive and debilitating tropical climate could no longer be justified.
In 1888, the Army turned the fort over to the Marine-Hospital Service to be operated as a quarantine station. On January 4, 1935, President Franklin D. Roosevelt, who visited the area by ship, designated the area as Fort Jefferson National Monument.