Fort Myers was named in honor of Colonel Abraham C. Myers during the Seminole Indian War, one of the first forts built when Florida became a US Territory in 1821, and the ensuing wave of settlers asked for protection from the native Seminoles. Although the fort was abandoned in 1858, during the Civil War it was reoccupied by Federal troops from 1863-1865. This was the site of the southernmost battle of the Civil War, a skirmish between Northern and Southern troops on Feb. 20, 1865 which is reenacted annually at the North Fort Myers Cracker Festival.

Herds of cattle were driven past the fort grounds to Punta Rassa, where they were lifted onto schooners and steamers and shipped to Cuba. Cattle, farming, and logging were early mainstays in the Fort Myers area. Sanibel Island grew Tomatoes, avocados, and castor beans and many pineapple plantations flourished inland along the river.

In 1885, Thomas Edison was visiting the area and was captivated with what he saw. Edison built a winter home and laboratory, Seminole Lodge, on the banks of the Caloosahatchee River. Edison then convinced his friend Henry Ford to build a winter home adjacent to his. Edison became Fort Myers' most famous resident and a strong force in its growth and development, and imported 200 Royal Palm trees from Cuba, giving the city the nickname of "The City of Palms."

The growth of the community was greatly spurred in 1904 with the arrival of the Coast Railroad, with its terminus at a dock on Monroe Street. Construction also began on the Bradford Hotel which still stands on First Street. One of Edison's new power plants, several banks, commercial ice plants and new hotels were built at this time. After World War II, many of the pilots who trained in the Fort Myers area returned to make their homes.