In 1830, when the Randolph-Macon College was founded by a Virginia Conference of the Methodist Church in Boydton, Virginia, it was named after two non-Methodists John Randolph, a Virginia statesman, and Nathaniel Macon, a North Carolina Statesman. The conference wanted to show that the college was not to be intended for only those following the Methodist faith by naming it after two non-Methodists.
During the U.S. Civil War many buildings within the town of Ashland, Virginia were damaged or destroyed. After the war in 1868, Randolph-Macon moved their main campus to Ashland and used an old hotel and other buildings for the campus.
A historical marker was placed near the current site of the college in Ashland.
David Alan Brat was an economics professor at Randolph-Macon College before he won his historic primary race against the GOP Majority Leader Eric Cantor. David Brat was the first non-incumbent, within the same party, to win against a standing House Majority Leader in over 100 years. Brat lost his seat in 2018 and is now the Liberty University Dean for the School of Business.