It is named in honor of General John Clarke of Georgia, who was later elected governor of that state.

For thousands of years, this area was occupied along the rivers by varying cultures of indigenous peoples.

At the time of European encounter, Clarke County was the traditional home of the Choctaw and the Creek people.

In 1805, by the Treaty of Mount Dexter, the Choctaw conveyed large amounts of land in what is now southeastern Mississippi and southwestern Alabama, including much of the western portion of Clarke County, to the United States for settlement by European Americans.

In 1892, Clarke County was the scene of a violent confrontation around economic divides that later became known as the Mitcham War.

[7] In the first decade of the 21st century, the county's largest communities voted to legalize alcohol sales: Jackson on May 10, 2005; Thomasville on August 14, 2007; and Grove Hill on November 3, 2009.

[10] During the Civil War, the county was notable for its salt production due to the naval blockade of southern ports.

[22] School districts include:[23] Since 1960, the majority of Clarke County voters has mostly supported Republican candidates for the presidency, but party affiliations have changed.

Prior to the civil rights era, most whites were members of the Democratic Party, although they began to vote for Nixon and other Republican presidential candidates.

After the Civil War, many African Americans had joined the Republican Party, but they were essentially disenfranchised around the turn of the 20th century by state changes to its constitution and laws, making voter registration more difficult.

For some positions, white voters have sometimes continued to vote for state-level Democrats, such as Doug Jones in 2017.