Eppes was born in April 1772, the son of Francis Eppes and Elizabeth Wayles Eppes, whose half sister Martha Wayles Skelton married Thomas Jefferson. Born either in Chesterfield County or at the residence of his maternal grandfather, John Wayles, in Charles City County, Eppes grew up at Eppington, his father’s estate in Chesterfield. He studied successively at the Orange County academy of Walker Maury and at Hampden-Sydney College, where he received an AB in the first graduating class in 1786. Afterward he attended the College of William and Mary and studied privately with George Wythe.
Between April 1791 and April 1793 Eppes lived in the Philadelphia household of Thomas Jefferson, then secretary of state. Jefferson directed his studies, which included coursework in mathematics, science, and law at the College of Philadelphia (beginning later in 1791 part of the University of Pennsylvania). During the summer of 1791 Eppes copied the notes James Madison had made during the Constitutional Convention of 1787 for Jefferson’s reference and in order to produce a backup copy of that priceless record. Working under strict injunctions of secrecy, Jefferson and Eppes were evidently the only persons outside of Madison’s household who read the notes during Madison’s lifetime.
Eppes returned to Williamsburg in 1793 for further legal study at the moot court at William and Mary. He may have been admitted to the bar the following year, but for most of his adulthood he was, as he described himself, “nothing more than an ordinary manager of land” that he had inherited. On September 25, 1796, Eppes asked Jefferson for permission to marry his daughter Maria (also called Mary or Polly) Jefferson. Despite unexplained delays, Jefferson exclaimed in June of the following year that the match could not have suited him better “if I had had the whole earth free to have chosen a partner for her.” They were married at Monticello on October 13, 1797. Jefferson settled thirty-one slaves and his 819.25-acre Pantops plantation on them, although they never acted on Jefferson’s repeated urgings that they live there. Eppes’s parents also confirmed a gift to him and his heirs of additional slaves and 881 acres of land at Bermuda Hundred in Chesterfield County. Eppes and his wife had two daughters, both of whom died in childhood, and one son before she died at Monticello on April 17, 1804.
Eppes was commissioned a justice of the peace for Chesterfield County on May 30, 1797. He narrowly won one of two seats representing the county in the House of Delegates for the 1801–1802 session and won a second term the following year. Eppes served on the Committee for Courts of Justice during both assembly sessions and also sat on the Committee of Privileges and Elections during the second.
From 1803 until 1811 Eppes served four consecutive terms in the House of Representatives. His district consisted of Amelia, Chesterfield, Goochland, and Powhatan counties. Eppes faced no serious challenges for reelection and ran unopposed at least once. During the first session of the Eighth Congress (October 1803–March 1804) he served only on the Joint Committee for Enrolled Bills. For the remainder of the Eighth Congress and the Ninth Congress (1804–1807) he sat on the Committee of Elections. In the Tenth (1807–1809) and Eleventh Congresses (1809–1811) he sat on the Committee of Ways and Means, and in the latter congress he chaired that important body and was thus the leading legislative spokesman on fiscal affairs.
By 1807 Eppes had purchased Mill Brook, an estate of more than 1,500 acres in Buckingham and Cumberland counties. After he inherited a share of Eppington, he disposed of it in 1810 and his other land in Chesterfield County. Eppes discussed trading Pantops to Jefferson for land adjoining Jefferson’s Poplar Forest plantation in Bedford and Campbell counties, but instead he sold Pantops to Jefferson’s grandson Thomas Jefferson Randolph in 1817. After moving to Mill Brook in 1810, Eppes ran against John Randolph of Roanoke in three consecutive contests for the seat in the House of Representatives from Buckingham, Charlotte, Cumberland, and Prince Edward counties. In 1811 Randolph easily defeated him by a two-to-one margin. Two years later Eppes’s strong support for the War of 1812 propelled him to a narrow victory, but in 1815 Randolph reclaimed his seat by an even tighter margin of fewer than one hundred votes. During Eppes’s final term in the House (1813–1815), he again chaired the Committee of Ways and Means.
The General Assembly elected Eppes to the U.S. Senate twice, by a wide margin on December 7, 1815, when he declined the post, and in a closer vote on December 10, 1816, when he accepted it. He served from March 4, 1817, until he resigned because of ill health on December 4, 1819. Eppes sat on the Committees on Finance and on the District of Columbia, chairing the former from November 20, 1818, until his resignation.
Throughout his congressional service Eppes spoke regularly. He favored a robust brand of Jeffersonian republicanism, opposing a large peacetime army, the Bank of the United States, the issuance of paper money, and any involvement by the Supreme Court in settling boundary disputes between states. By 1813 Eppes had concluded that direct taxation was the best system of finance in theory and the worst in practice. He supported the embargo on foreign trade that Congress enacted in December 1807 (though he did not vote on the measure) and thought that it should have been replaced only with a declaration of war. At times Eppes acted as a functional equivalent of an administration floor leader for Jefferson and Madison, although during his own presidency Jefferson was at pains to avoid direct discussions of politics with his son-in-law, who boarded at the presidential residence.
Eppes challenged John Randolph of Roanoke to a duel after the latter called him a liar during congressional debates on February 27, 1811, but a reconciliation was arranged. Eppes had acted as the second to Representative George W. Campbell when he shot their fellow congressman Barent Gardenier in a duel in March 1808. After a quarrel with Jefferson’s other son-in-law, Thomas Mann Randolph, Eppes did not visit Monticello for several years. Something of a latitudinarian in religion, Eppes once stated in a letter to Jefferson that he “considered one Religion as good as another and no better.”
In Halifax, North Carolina, on April 15, 1809, Eppes married Martha Burke Jones, the daughter of Willie Jones, a prominent planter who had led that state’s opposition to ratification of the U.S. Constitution. They had four daughters and two sons. The Eppes estate became so greatly encumbered that after his death his eldest son filed a friendly lawsuit against Eppes’s widow to secure his inheritance. In his last years Eppes suffered from a variety of ailments. He complained of gout, pains in his head, and rheumatism that affected the use of his limbs, and he was reportedly deranged at intervals during his final months. Eppes recovered his reason before he died at Mill Brook on September 15, 1823. He was buried in the family cemetery there.