Florida became a US Territory in 1821, and the ensuing wave of settlers asked for protection from the native Seminoles. Fort Myers was built along the Caloosahatchee River as one of the first bases of operations during the Seminole Indian Wars. Fort Myers was named in honor of Colonel Abraham C. Myers, the son-in-law of the commander of Fort Brooke in Tampa.

The fort was abandoned in 1858 and reoccupied by Federal troops from 1863-1865. The Southernmost battle of the Civil War, a skirmish between Northern and Southern troops occurred across the river in 1865 and is reenacted annually at the North Fort Myers Cracker Festival.

The fort itself was disassembled, and some of the wood used in construction of some of the first buildings in what would become downtown Fort Myers. No more than ten families lived in the original town when it was platted in 1876.

By 1885 Fort Myers was bursting with pride and a bulging population of 349, the second largest town on Florida's Gulf Coast south of Cedar Key. That same year Thomas Alva Edison was cruising Florida's west coast and stopped to visit the village.

Captivated with what he saw, Edison built his home and laboratory, Seminole Lodge, on the banks of the Caloosatchee River. He subsequently became Fort Myers' most famous resident and a strong force in its growth and development.

Edison had a deep respect for nature, regarding it as an endless source of discovery. Through his sheer determination and dauntless efforts, the beauty and majesty of the royal palms lining Riverside Avenue (now McGregor Boulevard) were imported and planted, and would become the reason for the "City of Palms" nickname.