Reidsville was established in the early 19th century as an outpost and stop on the stage line that ran between Salisbury, North Carolina, and Danville, Virginia, and was originally known as Wright's Crossroads.

The community grew from a single home and inn owned by the family of Reuben Reid, a local farmer, businessman, justice of the peace and father of David S. Reid), into a thriving farming community primarily supporting tobacco production and cigarette manufacturing.

Reidsville was officially incorporated by the North Carolina State Legislature in 1873 and became a key location of the American Tobacco Company which employed large numbers of city and county residents.

The roots of Reidsville date back to the early 19th century when William Wright of the Little Troublesome Creek area owned a tavern and store on the road connecting Danville and Salem.

Reuben Reid of the Hogan's Creek area moved his family, including wife, Elizabeth Williams Settle, and son, David Settle Reid, to a 700-acre (2.8 km2) farm on the ridge between Wolf Island and Little Troublesome creeks in May 1814.

Reuben Reid became a successful farmer, operated a store and a public inn maintained in a private home and served the county as a constable and justice of the peace.

When the family secured a post office, aptly named Reidsville, in 1829, 16-year-old David Reid was appointed its first postmaster.

On November 26, 1858, William Lindsey of Pittsylvania County, Virginia, was high bidder for a 384-acre (1.55 km2) tract of land known as Reidsville.

The Reidsville Chamber of Commerce, established in 1923 by business leaders in the community, is now located downtown.

The downtown area of Reidsville was like many of its counterparts across the state in the 1970s, seeing a decline in business opportunities due to the emergence of malls and shopping centers.