Gadsden County was created in 1823. It was named for James Gadsden of South Carolina, who served as Andrew Jackson's aide-de-camp in Florida in 1818.

Gadsden is bordered on the north by Decatur and Seminole County, Georgia and on the northeast by Grady County, Georgia.  Leon County, Florida is on the east; Florida's Liberty and Calhoun County are to the southwest and Jackson County, Florida is northwest of Gadsden.