The original inhabitants of Cheraw were the Cheraw and Pee Dee tribes. The Cheraw tribe lived near the river hill, which was across the banks of the Pee Dee River near present day Cheraw, but by the 1730s they had been devastated by disease. They joined the Catawba Confederacy leaving behind their name. Only a few scattered families were left behind by the time of the Revolution. There were a few settlers that came in the 1730s from the Welsh Baptist land grant by the British government in Society Hill. Many of the early settlers, around the 1740s, in Cheraw were English, Scottish, French, or Irish.

By 1750, Cheraw had become an established village with a growing river trade and was one of only six place South Carolina in So that appeared on English maps. In 1760, Joseph and Eli Kershaw were granted the part of Cheraw that is now the downtown historic district. The Kershaws laid out a formal street system and by 1830 all the streets were lined with rows of elms. The Kershaws originally called the town Chatham but people never accepted this name, continuing to call it Cheraw or Cheraw Hill. It was incorporated as a town in 1820, the same year the first bridge was built across the Pee Dee River. This brought the steamship business to Cheraw and along with it prosperity.

The main crops from the Cheraw area were corn, cotton, tobacco, rice and indigo. Cheraw was the largest cotton market between Georgetown and Wilmington. It boasted the largest bank in South Carolina outside of Charleston before the Civil War. However, in 1835 a serious fire destroyed most of the business district, but by 1850 the town had rebounded.

Leading up to the American Civil War, Cheraw citizens played a key role in South Carolina’s Secession from the Union. On November 19, 1860 the first call for secession in a public meeting was made at the Chesterfield County Courthouse. John A. Inglis of Cheraw was in attendance and introduced the resolution for South Carolina to secede. Inglis was also named the chairman of the committee that wrote the document for South Carolina’s secession.