Macon County was formed in 1842 from parts of Smith and Sumner counties. It was named in honor of the late Revolutionary War veteran and United States Senator, Nathaniel Macon. The county seat was named in honor of the Marquis de Lafayette.

Unlike adjacent counties of Middle Tennessee, which were generally pro-Confederate, but like neighboring counties in Kentucky, Macon County was largely pro-Union during the Civil War. In Tennessee's Ordinance of Secession referendum on June 8, 1861, Macon County voted to remain in the Union by a margin of 697 to 447. Macon was one of only eight counties in West or Middle Tennessee to support the Union. Earlier on February 9, 1861, Macon County voters had voted against holding a secession convention by a margin of 960 to 73. Many Macon Countians served in Kentucky Union regiments, especially the Ninth Infantry Regiment, because secessionists in surrounding Tennessee counties drove them over the state line.

The county's second-largest city, Red Boiling Springs, thrived as a mineral springs resort in the late 19th and early 20th centuries. Three hotels from this period — the Donoho Hotel, the Thomas House Hotel (previously the Cloyd Hotel), and the Armour's Hotel (previously the Counts Hotel) — are still open, though only the Armour's still offers mineral water treatments.