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. A Revolutionary War skirmish took place in 1781 at Ratcliff’s 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.

In 1803, John Fraser built the first school in Bishopville. In 1839, Bishopville Academy was established. During the early 1800s, Presbyterian minister, Julius DuBose, established a girls’ school. The school failed financially and by 1849, a school called the Bradford Springs Female Institute was in operation. It too failed. In 1853, Reverend Gilbert Morgan, of North Carolina bought the property and established Harmony Female College. The college continued operation until 1863, when the main building was destroyed by fire. In 1924, the last building was also destroyed by a fire.

The county is mainly rural and has been historically a leader in cotton production in the state. The two major towns are Bishopville, the county seat and Lynchburg.