Wilkes was unique in being made up of land ceded in 1773 by the indigenous Creek and Cherokee Native American nations in their respective Treaties of Augusta.

Wilkes also contributed part of the lands used in the creation of Madison, Warren, Taliaferro, Hart, McDuffie, and Greene Counties.

[6] Wilkes County was the site of one of the most important battles of the American Revolutionary War to be fought in Georgia.

[7] During the eighteenth and nineteenth centuries, colonists depended on enslaved African-American workers and whites to clear land, develop plantations, and cultivate and process cotton in this area.

Settlers increased pressure on the federal government to remove Native Americans from the region, including the Five Civilized Tribes from the Southeast.

In 1794, Revolutionary War veteran Elijah Clarke, led a group of men from Wilkes County into traditionally Creek lands and established a town and several forts and called it the Trans-Oconee Republic.

[14] Changes in agriculture through mechanization, the Great Depression, and a mass migration of African Americans from the area in the mid-20th century have resulted in a decline of population in the rural county since 1930.