Macon County is named in honor of General Nathaniel Macon, a North Carolina statesman and president pro tempore of the U.S. Senate. Macon County was carved from Houston and Marion counties in 1837.

Andersonville National Cemetery and Park is in the southwest tip of Macon County. Approximately 45,000 Union soldiers were imprisoned here during the Civil War, with 13,000 perishing from hunger and disease.