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Gainesville was established as “Mule Camp Springs” by European-American settlers in the early 1800s. Less than three years after the organization of Hall County on December 15, 1818, Mule Camp Springs was renamed “Gainesville” on April 21, 1821. It was named in honor of General Edmund P. Gaines, a hero of the War of 1812 and a noted military surveyor and road-builder. Gainesville was selected to be the county seat and chartered by the Georgia General Assembly on November 30, 1821.

A gold rush that began in nearby Lumpkin County in the 1830s resulted in an increase in the number of settlers and the beginning of a business community. In the middle of the 19th century, Gainesville had two important events. In 1849, it became established as a resort center, with people attracted to the springs. In 1851, much of the small city was destroyed by fire.

After the Civil War, Gainesville began to grow from 1870. In 1871 The Atlanta and Richmond Air-Line Railway, later re-organized into The Atlanta and Charlotte Air Line Railroad, began to stop in Gainesville, increasing its ties to other markets and stimulating business and population. It grew from 1,000 in 1870, to over 5,000 by 1900.