History denotes that in 1540 Hernando De Soto penetrated to the Arkansas River and perhaps well into Southeast Missouri, populated only by various Indian tribes. Under the pressure of a constantly advancing white immigration, the Indians were forced to retreat further westward to survive.

The entire area of Southeast Missouri was noted for its level swampy lowlands, subject to the overflow of the Mississippi River during periods of excessively heavy rainfall.

Virgin forests attracted the timber barons who demanded the forests. Following the clearing of the land, levees were built and drainage districts were formed. As hundreds of miles of levees and dykes were constructed within the drainage districts, thousands of acres of land were reclaimed for agriculture use. The reclaimed land, made especially rich by centuries of floods from the Mississippi River, was excellent farm land for corn, wheat, cotton, and later soybeans.

Mississippi County is located in what was formerly known as "Tywappity Bottom", a vast area bordered by the Scott County Hills on the north, St. James Bayou on the south, the Mississippi River on the east and Little River on the west.

By 1820 settlements had been made in most of the present counties of Southeast Missouri. The settlers, largely farmers, came from Illinois, Kentucky, Tennessee, and Virginia, in search for fertile and cheap land which they found around Charleston.

The site of the present City of Charleston was originally entered in 1830. In 1837, a person by the name of Thankful Randol sold Joseph Moore 22 1/2 acres of land and the City of Charleston was immediately laid out. Its original boundary was 12 blocks - four north and south and three east and west. The Original Plat was filed on May 20, 1837. An act to incorporate the City of Charleston, Missouri, in the County of Mississippi, was enacted by the General Assembly of the State of Missouri on March 25, 1872.