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Spain originally had colonial influence in Florida, succeeded by Great Britain and lastly the United States.

During the Second Seminole War, between 1835 and 1842, the U.S. Army operated Fort Dulany at Punta Rassa, at the mouth of the Caloosahatchee River. When a hurricane destroyed Fort Dulany in October 1841, army operations were moved up the Caloosahatchee River to a site named Fort Harvie. Fort Harvie was abandoned in 1842, as the Second Seminole War wound down. After a white trader was killed by Seminoles on the Peace River in 1849, the Army returned to the Caloosahatchee River in 1850. The new Fort Myers was built on the burned ruins of Fort Harvie. The fort was named for Brevet Colonel Abraham Charles Myers, quartermaster for the Army's Department of Florida. It covered about 139 acres (56 ha), and soon had 57 buildings, including a two-story blockhouse that was pictured in Frank Leslie's Illustrated Newspaper, and a 1,000-foot-long (300 m) wharf at which ships could dock. Irvin Solomon notes that Fort Myers was described "as 'one of the finest and largest' forts of the Seminole Wars". It was abandoned in 1858, at the end of the Third Seminole War.

During the American Civil War, Confederate blockade runners and cattle ranchers were based in Fort Myers. These settlers prospered through trading with the Seminole and Union soldiers.

The United States Army set up a camp on Useppa Island, near the entrance to Charlotte Harbor, in December 1863. It was intended as a place from which to recruit Union sympathizers and Confederate deserters and conscription-evaders and to raid into the interior and interfere with Confederate efforts to round up cattle for supply to the Confederate Army. After some probes along the Peace and Myakka rivers, which had mixed results, operations were moved to the mainland. Troops from the 47th Pennsylvania Infantry Regiment and the 2nd Regiment of Florida Rangers (later reorganized as the 2nd Florida Cavalry Regiment) left Key West for Fort Myers early in January 1864. The Union soldiers reached Fort Myers quickly enough to capture three Confederate sympathizers before they could act on orders to burn the fort to keep it out of Union hands. Beyond the principal cause for occupying the fort of providing support for Union sympathizers and local residents disaffected with Confederate taxation and conscription, the fort provided access to the large cattle herds in southern Florida, support for the blockade of the southwest Florida coast being conducted by the U.S. Navy, and a haven for any escaped slaves in the area.

In April 1864, after the troops from the 47th Pennsylvania Infantry Regiment had been transferred to Louisiana, Companies D and I of the 2nd United States Colored Infantry Regiment were transferred from Key West to Fort Myers, and remained at the fort until it was abandoned. Company G of the regiment had also been sent to Fort Myers by early May. Solomon argues that Brevet Brigadier General Daniel Phineas Woodbury, commandant of the District of Key West and the Tortugas, intended that action to be an irritant to the Confederacy. The presence of the black soldiers, who made up the majority of troops used in raids into Confederate territory, played on Confederate fears of armed blacks. It was reported that Woodbury took pleasure in placing a "prickly pear cactus under the Confederate saddle".

By the spring of 1864, Fort Myers was protected by a 500-foot-long (150 m) breastwork, 7 feet (2.1 m) high and 15 feet (4.6 m) wide, extending in an arc around the land side of the fort. The Seminole War-era blockhouse had been repaired and another two-story blockhouse built. The fort was soon harboring more than 400 civilians and Confederate army deserters. Many of the white men enlisted in the 2nd Florida Union Cavalry. Although designated as cavalry, the members of the regiment stationed at Fort Myers were never mounted. Escaped slaves that came to the fort were recruited into the 2nd United States Colored Infantry Regiment.

The Union achieved control of the full length of the Mississippi River after the fall of Vicksburg in July 1863. The Confederate Army then became dependent on Florida for most of its supply of beef. By the end of 1863 between 1,000 and 2,000 head of cattle were being shipped to the Confederate Army from Florida every week. As 1864 progressed, Union troops and sympathizers began driving cattle to Punta Rassa to supply Union ships on blockade duty and Union-held Key West, reducing the supply of cattle available to Confederate forces. The increased shipping from Punta Rassa led the Union Army to built a barracks and a wharf there. By one Confederate estimate, the Union shipped 4,500 head of cattle from Punta Rassa.

The Battle of Fort Myers was fought on February 20, 1865, in Lee County, Florida during the last months of the American Civil War. This small engagement is known as the "southernmost land battle of the Civil War." However, see Battle of Palmito Ranch.

The Fort Myers community was founded after the American Civil War by Captain Manuel A. Gonzalez on February 21, 1866. Captain Gonzalez was familiar with the area as a result of his years of service delivering mail and supplies to the Union Army at the fort during the Seminole Indian Wars and Civil War. When the U.S. government abandoned the fort following the Civil War, Gonzalez sailed from Key West to found the community. Three weeks later, Joseph Vivas and his wife, Christianna Stirrup Vivas, arrived with Gonzalez's wife, Evalina, and daughter Mary.

Gonzalez settled his family near the abandoned Fort Myers, where he began the area's first trading post. He traded tobacco, beads, and gunpowder, and sold otter, bobcat, and gator hide to the neighboring Seminole. A small community began to form around the trading post.

In the late 19th century, northerners began to travel to Florida in the winter. Some saw development opportunities. In 1881, the wealthy industrialist Hamilton Disston of Philadelphia, Pennsylvania came to the Caloosahatchee Valley. He planned to dredge and drain the Everglades for development. Diston connected Lake Okeechobee with the Caloosahatchee River; this allowed steamboats to run from the Gulf of Mexico to Lake Okeechobee and up the Kissimmee River.

On August 12, 1885, the small town of Fort Myers—all 349 residents—was incorporated. At that time, it was the second-largest town on Florida's Gulf Coast south of Cedar Key.

In 1885, inventor Thomas Alva Edison was cruising Florida's west coast and stopped to visit Fort Myers. He soon bought 13 acres along the Caloosahatchee River in town. There he built his home "Seminole Lodge", as a winter retreat. It included a laboratory for his continuing work. After the lodge was completed in 1886, Edison and his wife, Mina, spent many winters in Fort Myers. Edison also enjoyed local recreational fishing, for which Fort Myers had gained a national reputation.

In 1898, the Royal Palm Hotel was constructed. This luxury hotel attracted tourists and established Fort Myers nationally as a winter resort destination.

On May 10, 1904, access to the Fort Myers area was greatly improved with the opening of the Atlantic Coast Line Railroad, connecting Punta Gorda to Fort Myers. This route provided Lee County both passenger and freight railroad service.

In 1908, the Arcade Theater was constructed in Downtown Fort Myers. Originally a vaudeville house, Edison viewed films here for the first time with friends Henry Ford and Harvey Firestone. With the growth of the film industry, the Arcade Theatre was converted into a full movie house. A wall divided the stage in order to form two screening rooms. Changes in moviegoing habits since the late 20th century have led to the renovation of the theater for use again in live performance. It is now host to the Florida Repertory Theatre, a performing arts hall.

During World War I, Edison became concerned about America's reliance on foreign supplies of rubber. He partnered with tire producer Harvey Firestone (of the Firestone Tire and Rubber Company) and Henry Ford (of the Ford Motor Company) to try to find a rubber tree or plant that could grow quickly in the United States. He sought one that would contain enough latex to support his research endeavor. In 1927, the three men contributed $25,000 each, and created the Edison Botanic Research Corporation in an attempt to find a solution to this problem. In 1928, the Edison Botanic Research Corporation laboratory was constructed. It was in Fort Myers that Edison conducted the majority of his research and planted exotic plants and trees. He sent results and sample rubber residues to West Orange, New Jersey, for further work at his large Thomas A. Edison "Invention Factory" (now preserved in the Thomas Edison National Historical Park). Through Edison's efforts, the royal palms lining Riverside Avenue (now McGregor Boulevard) were imported and planted. They inspired Fort Myers' nickname as "City of Palms".

After testing 17,000 plant samples, Edison eventually discovered a source in the goldenrod plat (Solidago leavenworthii). The rubber project was transferred to the United States Department of Agriculture five years later.

In 1916, automobile magnate Ford purchased the home next to Edison's from Robert Smith of New York. Ford named his estate "the Mangoes". Ford's craftsman-style "bungalow" was built in 1911 by Smith. Ford, Firestone, and Edison were leaders in American industry and part of an exclusive group titled "the Millionaires' Club". The three men have been memorialized in statues in downtown Fort Myers' Centennial Park.

In 1924, with the beginning of construction of the Edison Bridge, named for Edison, the city's population steadily grew. The bridge was opened on February 11, 1931, the 84th birthday of its namesake. Edison dedicated the bridge, and was the first to drive across it.

In the decade following the bridge's construction, the city had a real estate boom. Several new residential subdivisions were built beyond downtown, including Dean Park, Edison Park, and Seminole Park. Edison Park, located across McGregor Boulevard from the Edison and Ford properties, includes a number of Fort Myers' most stately homes. The historic development showcases a variety of architectural styles. In the 21st century, it is known for its community activities and strong neighborhood ties.

In 1947, Mina Edison deeded Seminole Lodge to the city of Fort Myers, in memory of her late husband and for the enjoyment of the public. By 1988, the adjacent Henry Ford winter estate was purchased by the city and opened for public tours in 1990. The combined properties today are known as the Edison and Ford Winter Estates.

According to the United States Census Bureau, the city has a total area of 40.4 square miles (105 km²), of which 31.8 square miles (82 km²) is land and 8.6 square miles (22 km²) (21.25%) is water.

Fort Myers is on the border between a tropical monsoon climate (Am) and a humid subtropical climate (Cfa).

The temperature rarely rises to 100 °F (38 °C) or lowers to the freezing mark. Rainfall averages just over 56 inches per year, strongly concentrated during the rainy season (June to September) with its frequent showers and thunderstorms; on average, these four months deliver 68 percent of annual rainfall. From October to May, average monthly rainfall is less than three inches. In years with drier than average conditions from winter into mid-spring, drought can develop, and brush fires can be a significant threat. Reflecting the June to September wet season, Fort Myers has 89 days annually in which a thunderstorm is close enough for thunder to be heard, the most in the nation.

The monthly daily average temperature ranges from 64.5 °F (18.1 °C) in January to 83.4 °F (28.6 °C) in August, with the annual mean being 75.1 °F (23.9 °C).

Records range from 24 °F (−4 °C) on December 29, 1894 up to 103 °F (39 °C) on June 16–17, 1981.

The population of Fort Myers was 62,298 at the 2010 census. Between the 2000 census and 2010 census, the city's population increased at a rate of 29.2 percent.

Fort Myers is one of two cities that make up the Cape Coral-Fort Myers Metropolitan Statistical Area. The 2010 population for the metropolitan area was 618,754.

The population of Lee County, Florida and the Cape Coral-Fort Myers Metropolitan Statistical Area has grown 40.3 percent since the census in 2000, much faster than the average growth rate of 17.6 percent experienced throughout the State of Florida.