The Mayaca or Jororo Indians inhabited the shores of Lake Monroe at the time of European contact. By 1760, however, war and disease had decimated the tribe, which would be replaced by the Seminole. Florida was acquired by the United States from Spain in 1821, but the Seminole Wars would delay settlement.
In 1835, during the Second Seminole War the port of Palatka on the St. Johns River, then the major artery into Central Florida from the East Coast, was burned. Consequently, a U.S. Army garrison was established upstream, on the southern side of Lake Monroe near a trading post. Established as Camp Monroe in 1836, the site was enclosed by log breastwork on three sides but open to the river, with approximately 300 men based there. The camp was attacked by allied Seminoles on February 8, 1837. It would be strengthened and renamed Fort Mellon in honor of Captain Charles Mellon, the sole American casualty of the attack. During the war, General Zachary Taylor had a road built connecting a string of military defenses from Lake Monroe to Fort Brooke (now Tampa).
The town of Mellonville was founded around Fort Mellon in 1842 by Daniel Stewart. In 1845, Florida became a U.S. state. That same year, Mosquito County was renamed Orange County and the county seat was moved from Enterprise to Mellonville. Orange groves were planted, with the first fruit packing plant built in 1869.
In 1870, "General" Henry Shelton Sanford bought 12,548 acres (50.78 km2) to the west of Mellonville and laid out the community of Sanford. Believing it would become a transportation hub, he called it "The Gateway City to South Florida." Sanford imported two colonies of Swedes (totaling about 150 adults) as indentured servants to labor a year for their travel expenses. The Swedes would do the back-breaking work of establishing a new town and clearing the sub-tropical wilderness in advance of creating a citrus empire, arriving by steamboat in 1871.