Madison county is located on the southeastern edge of the Bluegrass region of Kentucky where the knobs mark the boundary between the rolling Bluegrass and the hillier Cumberland Plateau. The county was formed in 1785 while a part of Virginia. The original county seat was Milford, but it was later moved to Richmond.

Many early settlers passed through Madison county. Fort Boonesborough was established near the Kentucky River in 1775. Several ferries once operated in the county, beginning with one at Boonesborough in 1779. A ferry still operates at Valley View, where Tates Creek enters the Kentucky River.

Madison county is the home of the Lexington-Blue Grass Army Depot, Eastern Kentucky University at Richmond, and Berea College in Berea.