Fort Jefferson was built to protect one of the most strategic deepwater anchorages in North America. By fortifying this spacious harbor, the United States maintained an important “advance post” for ships patrolling the Gulf of Mexico and the Straits of Florida. Nestled within the islands and shoals that make up the Dry Tortugas, the harbor offered ships the chance to re– supply, refit, or seek refuge from storms. The location of the Tortugas along one the world’s busiest shipping lanes was its greatest military asset. Though passing ships could easily avoid the largest of Fort Jefferson’s guns, they could not avoid the warships that used its harbor.

The design of the fort called for a three-tiered six-sided 420 heavy-gun fort, with two sides measuring 325 feet, and four sides measuring 477 feet. The walls met at corner bastions, which are large projections designed to allow defensive fire along the faces of the walls they joined. The heavy guns were mounted inside the walls in a string of open casemates, or gunrooms, facing outward toward the sea through large openings called embrasures. Fort Jefferson was designed to be a massive gun platform, impervious to assault, and able to destroy any enemy ships foolhardy enough to come within range of its powerful guns.

Living quarters for soldiers and officers, gunpowder magazines, storehouses, and other buildings required to maintain the fort were located on the parade ground inside the fort's massive brick walls. The Army employed civilian machinists, carpenters, blacksmiths, masons, general laborers, the resident prisoner population, and slaves to help construct the fort. By 1863, during the Civil War, the number of military convicts at Fort Jefferson had increased so significantly that slaves were no longer needed. At the time, there were 22 black slaves employed on the project.

Fort Jefferson's peak military population was 1,729. In addition, a number of officers brought their families, and a limited number of enlisted personnel brought wives who served as laundresses (typically four per company). There were also lighthouse keepers and their families, cooks, a civilian doctor and his family, and others. In all, there were close to 2,000 people at Fort Jefferson during its peak years.

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.