Gainesville, named in honor of Seminole Indian War General Edmund P. Gaines, was founded on September 6, 1853. The original city plat followed a traditional gridiron design; placed in dry and high land, the city covered approximately eight blocks surrounding a courthouse square. The first courthouse, a two-story wooden structure, and the first school were built in 1856, and the first passenger train arrived on April 21, 1859. By 1860 the town's population had reached 269 and the downtown included a general store and three hotels.

The civil War slowed this development as the town became the site of a Confederate storehouse. Two encounters with Federal troops occurred here: the first, a skirmish on February 15, 1864, and the second, a battle on August 17, 1864. At this battle near the square, Captain Jonathan J. Dickinson and the Second Florida Cavalry routed the Union forces. Nearly all the attackers were either killed or captured. Many townspeople viewed the fighting from the windows of the Beville house near downtown.

After the war, education thrived as Gainesville Academy, the town's first school, combined with Ocala's East Florida Seminary in 1866. The first black school, the Union Academy, opened its doors in 1867. On April 14, 1869, Gainesville was incorporated, making that date its official birthday.

The Northeast especially became an elite residential neighborhood. From 1909 to 1950 four University of Florida presidents had homes here, making the Northeast a center for social and intellectual life in the town. In 1910 William Reuben Thomas moved into Gainesville's most elaborate private residence, the "Sunkist Villa", situated near Sweetwater Branch. The surrounding areas continued to develop in the 1920's with the building of the Thomas Hotel and the establishment of the Highlands and Duck Pond area. The city's growth was not confined to the white community alone. Freedmen settled primarily in the western half of the Brush Addition to Gainesville (the Pleasant Street area) and in the Olivia A. Porter's subdivision in the southwest. Many of these early settlers came from South Carolina and were skilled tradesmen, preachers, and teachers. The neighborhoods they inhabited still remain important historic and architectural resources. The concentration of folk housing there represents a uniquely preserved example of the social, economic, and cultural traditions of Gainesville's black community.

The university's emergence as an important economic factor in the community helped the city to survive the collapse of the local cotton and phosphate industries during World War I. Throughout the 1920's and 1930'a new neighborhoods like College Park, Hibiscus Park, and Golf View developed around the University and drew the city westward. Following World War II the University greatly expanded, as population growth continued in the northwest and southwest areas, away from downtown. Trees and landscaped medians were sacrificed for traffic lanes, while large homes near downtown like the Colclough and Baird mansions were destroyed and supplanted by law offices, banks, and parking lots.