Jefferson married Martha Wayles Skelton in 1772. They had six children together, but only two, Martha (Patsy) and Mary (Polly), survived to adulthood. Their marriage appears to have been a loving one. Martha's early death in 1782 devastated Thomas, and he never remarried.

Martha Wayles Jefferson died on September 6, 1782, after a difficult pregnancy. Her death deeply affected Jefferson, who was reportedly heartbroken by the loss of his wife. He never remarried and dedicated himself to raising their children.

Jefferson's relationship with Sally Hemings, an enslaved woman who was the half-sister of his deceased wife, has been a subject of intense historical debate. DNA evidence and historical analysis strongly suggest that Jefferson fathered at least one, and likely all, of Hemings' children. This relationship presents a complex and troubling aspect of Jefferson's life and raises questions about his views on race and slavery. While historical evidence has grown substantially, the nature of their relationship and the role consent played are still debated.

Jefferson had a very close relationship with his daughter Martha. Following his wife's death, she took on the role of hostess for him at Monticello, and travelled to France to be with her father during his time as ambassador. She often copied letters for Jefferson, and was a lifelong companion.

Mary Jefferson Eppes was Thomas's younger daughter who died soon after giving birth. She died from complications and her loss greatly saddened Jefferson, who relied on her support and companionship. Jefferson was very close to his grandson Francis Wayles Eppes, after the death of Mary.

Jefferson enjoyed spending time with his grandchildren at Monticello. They brought joy and companionship to his later years. The management of his estate and the well-being of his family were important concerns during his retirement.