Clayton County was formed in 1858 from parts of Fayette and Henry counties. Georgia 's 125th county was named for Judge Augustin S. Clayton, who held the county's first sessions of the superior court and later served in both the Georgia House of Representatives and Senate.

Jonesboro , the county seat, was originally called Leaksville. When the Central Railroad line reached the town, the name was changed to honor Captain Samuel G. Jones, one of the line's surveying engineers.