The first removal treaty carried out under the Indian Removal Act was the 1830 Treaty of Dancing Rabbit Creek, by which the Choctaw ceded about 11 million acres of the Choctaw Nation (now Mississippi) to the United States in exchange for about 15 million acres in Indian Territory (now Oklahoma).

Benjamin Grubb Humphreys, a state senator from Claiborne County, Mississippi, is credited with the founding of Itta Bena.

Following several crop failures in the 1850s at his home in Claiborne County, Humphreys took a trip by river steamer up into the Yazoo wilderness to look for a new farming opportunity in the former Choctaw area.

[4] He found such an opportunity on Roebuck Lake, a stretch of old channel that the river had discarded a few miles west of Greenwood, in what was then Sunflower County.

Bringing a group of slaves up from his plantations during the winter, when boats could use high water to pass from the Yazoo into Roebuck, he directed them in clearing timber and brush from the overgrown bottomland to develop agricultural fields for cultivation of cotton.

Longtime Claiborne County friends became interested in his project, and others began to acquire land in the area two years later.

Planters used the Yazoo River to ship cotton downriver, ultimately to New Orleans for transport to markets in the United States and Great Britain.

The town’s first school, a one-room building only for white students, was built in 1888 and Emma Cross served as the first teacher.

The white minority dominated politics and the economy, as the state legislature essentially disenfranchised blacks by the constitution of 1890.

On a march in 1966 between Itta Bena and nearby Greenwood, coordinated by the SNCC but led by Martin Luther King Jr., Stokely Carmichael coined the rallying phrase "Black power!".

Byron De La Beckwith, known as the murderer of Medgar Evers, drove his truck by the marchers three times while the local police looked on.

Mississippi Valley State University is located 1 mile (1.6 km) northwest of Itta Bena in unincorporated Leflore County.

[11] The Mississippi Valley State Delta Devils football team play at Itta Bena's 10,000-seat Rice–Totten Stadium.