Lee County was named for Confederate general Robert E. Lee (1807-1870). The county was formed in 1902 from parts of Darlington, Kershaw, and Sumter counties, and the county seat is Bishopville.

A Revolutionary War skirmish took place in 1781 at Ratcliffs Bridge, and during the Civil War Confederate and Union troops skirmished at Mount Elon and Spring Hill in 1865. Lee County was also the site in 1880 of the last fatal duel fought in South Carolina.

Cotton farming has long been associated with this area. U. S. Senator Ellison Durant Smith (1864-1944), a native of Lee County, was nicknamed Cotton Ed because of his support for cotton farmers.