Indian artifacts collected in DeSoto County link it with prehistoric groups of Woodland and Mississippian culture peoples.

Based on records of the expedition and archeology, the National Park Service has designated a "DeSoto Corridor" from Coahoma County, Mississippi to the Chickasaw Bluff in Memphis.

The town named Chicasa, which De Soto visited, was probably the ancestral home of the historical Chickasaw, who are descended from the Mississippian culture.

The Chickasaw Nation regarded much of western present-day Tennessee and northern Mississippi as their traditional hunting grounds.

However, France ceded its claim to territories east of the Mississippi River to Britain in 1763, after having been defeated in the Seven Years' War.

Negotiations began in September 1816 between the United States government and the Chickasaw nation and concluded with the signing of the Treaty of Pontotoc in October 1832.

During and after the Civil War, the area was developed as large plantations by planters for cultivation of cotton, a leading commodity crop.

After the war and emancipation, many freedmen stayed in the area, but shaped their own lives by working on small plots as sharecroppers or tenant farmers, rather than on large labor gangs on the plantations.

In 1890, the state legislature disenfranchised most blacks under the new constitution, which used poll taxes and literacy tests to raise barriers to voter registration.

In 1935, a white lynch mob attacked early union organizer and minister Reverend T. A. Allen, shot him, and threw him into the Coldwater River.

[8] Since the late 20th century, DeSoto County has experienced considerable suburban development related to the growth of Memphis.

Some observers have characterized the shift as black flight, but it is also typical of the pattern of postwar suburban growth in which people who could afford it moved to newer housing in suburbs.

[9] Such suburban residential development in the county has been most noticeable in the Mississippi cities of Southaven, Olive Branch, and Horn Lake.

Also stimulating development in the formerly rural area is the massive casino/resort complex, in the neighboring Tunica County, which is the sixth-largest gambling district in the United States.

According to the 2000 census,[21] the largest self-identified ancestry groups in DeSoto County were English 53.1%, Scots-Irish 15.1%, African 11.4%, and Irish 4.5%.

[22] DeSoto County was also previously known as the home of Maywood Beach, a water park that closed in 2003 after more than 70 years of operation.

Genevieve, Missouri, where many French settled after France ceded its territory east of the Mississippi to Great Britain following its defeat in the Seven Years' War.