Settlement of this area began in 1784 with a small group of Revolutionary War veterans and other pioneers who ventured into the newly ceded lands of Franklin County. The first permanent communities were on Sandy Creek at Groaning Rock, Yamacutah (near present-day Commerce), Hurricane Shoals, and in 1786 on the Middle Oconee River near the Tallassee Shoals.

The population had swelled to 350 by the time the county was formed by legislative act to February 1796.

County MapNamed for Revolutionary patriot and Georgia statesman James Jackson, the county originally covered 1800 square miles. However, from 1801 until 1914 portions were taken to form parts of the present counties of Clarke, Oconee, Madison, Gwinnett, Hall, Walton, Banks, and Barrow. Jackson County today contains only 337 square miles.

Jackson County experienced steady growth throughout the 19th century, largely due to the railroads that intersected the area. Many towns did not even exist until the tracks were laid and a depot constructed. Of the ten municipalities incorporated by 1920, seven defined their boundaries from the depot.

Of these, Harmony Grove became one of the leading distribution centers of northeast Georgia due to the railroad. The town was prospering so well that in 1904, the citizens changed the name to Commerce, "to better reflect the commercial air of a city."