In 1778, Mary (sometimes known as Maria) was born at Monticello. Her parents were Martha and Thomas Jefferson. When her mother died, Mary was only four years old. Jefferson sent Mary and her younger sister Lucy to live with their aunt, Elizabeth Wayles Eppes in Southside, Virginia.

Her father wrote Mary often. He was concerned about her schooling, asking "How goes the Spanish?" He was concerned about her life and happiness: "Tell me . . . how your uncle and aunt and the family do, and how you do yourself." During this time, Mary’s little sister Lucy died of whooping cough.

When Mary was eight years old, Jefferson arranged for his daughter to travel to France to be with him and her older sister, Martha. However, Mary had become attached to the Eppes family. Before leaving, she wrote her father "I don’t want to go to France, I had rather stay with Aunt Eppes."

Mary was nine years old when she arrived in Paris accompanied by Sally Hemings, an enslaved ladies maid. Jefferson relied on Martha to help raise her younger sister, "Teach her above all things to be good. Teach her to be true." In Paris, the two girls attended the same boarding school. Mary studied literature, drawing and music.

In 1797, Mary married John Wayles Eppes, her cousin. She gave birth to three children. Two died as infants. Only one son, Francis, lived to be an adult. Mary died after giving birth to a baby daughter, who died soon after. She was only twenty-six years old. Jefferson wrote to a friend that he had "lost even the half of what I had."