During the period of Indian Removal in the 1830s, he was one of the chiefs who signed the Treaty of Dancing Creek of 1830, by the terms of which the Choctaw sold to the US their remaining lands east of the Mississippi River.

Following the American Civil War, during Reconstruction the majority-black population of freedmen in the county gained emancipation and suffrage, participating for the first time in formal politics.

In the mid-1870s, the Red Shirts, a white paramilitary organization working on behalf of the Democratic Party, developed chapters in Mississippi.

One particular act of mass violence stands out: In September 1889, organizing by the Colored Farmers' Alliance sparked false rumors of an impending Black "uprising."

[6] Most occurred around the turn of the 20th century, as part of white imposition of Jim Crow conditions and suppression of black voting.

As with other parts of the majority-black Delta, Leflore County was a major site of activism and white violence during the Civil Rights Movement.

Till, a teenage African-American, was visiting from Chicago and staying with relatives in Money, where Bryant's Grocery and Meat Market was located.

Blacks had been essentially disfranchised since implementation of Mississippi's new constitution in 1890, establishing poll taxes, literacy tests and other voter registration barriers.

[9] The Student Nonviolent Coordinating Committee had moved its headquarters to Greenwood in early 1963, and by late March of that year, eight SNCC members were arrested while trying to register voters.

The United States Department of Justice Civil Rights Division filed suit against the city of Greenwood and Leflore County to obtain their release.

In June 1963, 45 residents of Itta Bena were arrested in Leflore County while protesting an attack on churches where voter registration drives were being held.

[10] Passage of national civil rights legislation by Congress in 1964 and 1965 began to change the ground rules, especially as it authorized federal oversight and enforcement in counties with a history of an under-representation of minority voters.

Major civil rights leaders and marchers from a variety of organizations vowed to continue his march of more than 220 miles from Memphis, Tennessee to Jackson, Mississippi.

After previous registration drives, the white county board had cut off federal commodity subsidies to the black community, threatening the survival of numerous poor families.

Other notable natives and one-time residents of the county were (in alphabetical order) David "Honeyboy" Edwards, Guitar Slim, Richard "Hacksaw" Harney, Luther Johnson (Guitar Junior), Robert Johnson, Rubin Lacey, Furry Lewis, Tommy McClennan, Dion Payton, Robert Petway, Brewer Phillips, Fenton Robinson, Hubert Sumlin, and Hound Dog Taylor.

[21][22] Mississippi Valley State University is located 1 mile (1.6 km) northwest of Itta Bena in an unincorporated area.