Mississippi County is a county located in the Bootheel of the U.S. state of Missouri, with its eastern border formed by the Mississippi River. As of the 2020 census, the population was 12,577. The largest city and county seat is Charleston. The county was officially organized on February 14, 1845, and was named after the Mississippi River.

The Missouri Bootheel is a salient (protrusion) located in the southeasternmost part of the U.S. state of Missouri, extending south of 36°30′ north latitude, so called because its shape in relation to the rest of the state resembles the heel of a boot. Strictly speaking, it is composed of some or all of the counties of Dunklin, New Madrid, and Pemiscot. However, the term is locally used to refer to the entire southeastern lowlands of Missouri located within the Mississippi Embayment, which includes parts of Butler, Mississippi, Ripley, Scott, Stoddard and extreme southern portions of Cape Girardeau and Bollinger counties. The largest city in the region is Kennett.