The construction of the fort began in 1846 and was planned and supervised by the U.S. Army Corps of Engineers. The labor force during the early years was made up predominantly of slaves from Key West. Although construction of the fort continued for 30 years it was never completed largely due to changes in weapon technology, which rendered it obsolete by 1862. After the Civil War, the fort was used as a federal prison. Among the prisoners kept there were several of the "Lincoln Conspirators." One of these was Dr. Samuel A. Mudd, the physician who set the broken leg of President Abraham Lincoln's assassin, John Wilkes Booth.
In 1867, during an outbreak of Yellow Fever, Dr. Mudd helped prison doctors fight the epidemic. Two years later the physician's sentence was commuted and he was released. The Department of the Army officially abandoned Fort Jefferson in 1874; established as Fort Jefferson National Monument in 1935, it was rededicated and renamed Dry Tortugas National Park on October 26, 1992.