[3][1] After being taught by tutors as was customary in his planter class, Eppes attended the University of Pennsylvania at Philadelphia, and graduated from Hampden–Sydney College in Virginia in 1786.

Eppes married his first cousin Mary Jefferson (known as "Polly" in childhood and "Maria" as an adult) on October 13, 1797, at Monticello.

[1] After Mary's death, Eppes moved his household and slaves from Mont Blanco to another of his plantations called Millbrook in Buckingham County, Virginia.

[7] She lived at Milbrook for the rest of her life,[9] and when she died in 1857, was buried next to John Wayles Eppes in the family cemetery there.

He chaired the Ways and Means Committee for the Eleventh Congress but lost his re-election attempt so did not serve in the Twelfth, but instead spent the next two years at his Milbrook plantation.