Madison County is a county located in the Lead Belt region of the U.S. state of Missouri. As of the 2020 census, the population was 12,626. Its county seat and largest city is Fredericktown. The county was officially organized on December 14, 1818, and was named after President James Madison. Mining has been a key industry in this area with Madison C…Madison County is a county located in the Lead Belt region of the U.S. state of Missouri. As of the 2020 census, the population was 12,626. Its county seat and largest city is Fredericktown. The county was officially organized on December 14, 1818, and was named after President James Madison. Mining has been a key industry in this area with Madison County recorded as having the oldest lead mine west of the Mississippi River.