Randolph-Macon was founded in 1830 by the Virginia Methodists, and is one of the oldest Methodist-run colleges in the country. It was originally located in Boydton, near the North Carolina border but as the railroad link to Boydton was destroyed during Civil War, the college's trustees decided to relocate the school to Ashland.

The college has a historical relationship with Randolph-Macon Woman's College in Lynchburg, Virginia. The Woman's College was founded under Randolph-Macon's original charter in 1893 by the then-president William Waugh Smith; it was intended as a female counterpart to Randolph-Macon. Randolph-Macon itself became co-educational in 1972 and the two schools are now governed by two separate boards.

In 1893, a number of preparatory schools--all called Randolph-Macon Academy--were founded. The only one which remains today is Randolph-Macon Academy in Front Royal, Virginia. Randolph-Macon Academy is today the only co-educational boarding school in the country affiliated with the United States Air Force Junior Reserve Officer Training Corps (JROTC).

It was in the news recently when 10-year-old Gregory R. Smith  enrolled at the college in September 1999. Smith graduated in 2003 cum laude with a degree in mathematics.