The county was officially organized on October 1, 1812, encompassing most of present-day Arkansas. Named after Nuevo Madrid, a district located in the region, the area was under Spanish rule following France's cession of Louisiana after being defeated in the Seven Years' War. The Spanish named the district after Madrid, the capital of Spain.
The county includes a large part of the New Madrid Fault that produced the 1811–12 New Madrid earthquakes. This zone remains geologically active, and had continued to produce smaller earthquakes with some frequency.
Cape Girardeau, New Madrid, St. Charles, St. Louis, Ste. Genevieve formed as original districts of Louisiana District of the Indiana Territory. Present day Missouri was a part of the Spanish Louisiana Territory, owned by Spain, until 1805. It then became part of the Louisiana Territory until the Missouri Territory was formed in 1812. The state was formed in 1821 and was much smaller than the territory.