[3][4] The area which is now Yazoo County was acquired by the State of Mississippi from the Choctaw Indians in 1820.

It was the 19th county established in the State of Mississippi, and remains the largest in area.

It was developed for cotton plantations, which lined the major river to have transportation access.

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

In 1900 a railroad disaster killed engineer Casey Jones; it took place in Yazoo County just north of Vaughan.

It experienced two accidents relating to carbon dioxide pipelines owned by Denbury Resources.

In 2011, a pipeline had a "blowout" in Tinsley, Mississippi, causing the sickening of one worker and killing deer, fish and birds.

As of the 2020 United States Census, there were 26,743 people, 8,542 households, and 5,203 families residing in the county.

Yazoo County, Mississippi has been featured in an Independent Lens series documenting bullying.