Sally Hemings was born to Elizabeth Hemings (1735-1807), the daughter of Susanna, an enslaved African, and John Hemings, an English sea captain. Susanna and Elizabeth Hemings (also known as Betty Hemings) were first held by Francis Eppes IV. John Hemings tried to buy them from Eppes, but he refused to give them up. The mother and daughter were inherited by Francis' daughter, Martha Eppes, who took them with her as personal servants upon her marriage to the planter John Wayles. Sally Hemings' paternal grandparents were Mr. Edward Wayles and Mrs. Ellen Ashburner-Wayles both of Lancaster, England. Her maternal grandparents were Mr. John Hemings and Ms. Susannah Epps.

After Martha's death, Wayles married and was widowed twice more. Several sources assert that the widower John Wayles took his slave Betty Hemings as a concubine and had six children by her during the last 12 years of his life; the youngest of these was Sally Hemings. They were half-siblings to his daughters; the first, Martha Wayles (named after her mother, John Wayles' first wife), married the young planter Thomas Jefferson.

The biracial children of Betty Hemings were three-quarters European in ancestry and very fair skinned. (They had a white (caucasian) maternal grandparent and two white paternal grandparents.) Since 1662 in Virginia, children born to enslaved mothers took their legal status as slaves under the principle of partus sequitur ventrem. According to the law, Elizabeth and her children, including Sally Hemings, and all their children, were legally slaves, even when the fathers were the white masters.

After Wayles died in 1773, his daughter Martha and Jefferson inherited the Hemings family as among 135 slaves from his estate, as well as 11,000 acres of land. The youngest Wayles-Hemings child was Sally, an infant that year and about 25 years younger than Martha. Scholars have noted that as the mixed-race Wayles-Hemings children grew up at Monticello, they were trained and given assignments as skilled artisans and domestic servants, at the top of the slave hierarchy. Betty Hemings' other children and their descendants, also mixed race, also had privileged assignments. None worked in the fields.

In 1784, the widower Thomas Jefferson was appointed the American envoy to France; he took his oldest daughter Martha (Patsy) with him to Paris, as well as some of his personal slaves. Among them was Hemings' older brother James Hemings, who became trained as a chef in French cuisine. His two younger daughters were in the care of friends in the US. After Lucy died of whooping cough in 1787, Jefferson sent for his surviving daughter, nine-year-old Maria (Polly) Jefferson, to live with him. The teenage slave Sally Hemings was chosen to accompany Polly to France.

Originally, Jefferson arranged for Polly to "be in the care of her nurse, a black woman, to whom she is confided with safety" [Letter from Thomas Jefferson to Abigail Adams, Dec. 21, 1786]. According to Abigail Adams, however, "The old Nurse whom you expected to have attended her, was sick and unable to come. She has a Girl about 15 or 16 with her" [Letter from Abigail Adams to Thomas Jefferson, June 26, 1787]. Polly and Sally stayed in London with Abigail and John Adams from June 26 until July 10, 1787, before Jefferson's associate, Mr. Petit, took the girls to Paris. In a letter to Jefferson on June 27, 1787, Abigail wrote, "The Girl who is with [Polly] is quite a child, and Captain Ramsey is of opinion will be of so little Service that he had better carry her back with him. But of this you will be a judge. She seems fond of the child and appears good naturd." On July 6, Abigail wrote to Jefferson, "The Girl she has with her, wants more care than the child, and is wholy incapable of looking properly after her, without some superiour to direct her."

Sally Hemings remained in France (where slavery was illegal) for 26 months. Jefferson paid wages to her and James while they were in Paris. He paid Sally Hemings the equivalent of $2 a month. In comparison, he paid his Parisian scullion $2.50 a month, and James Hemings $4 a month as chef in training. The French servants earned from $8 to $12 a month.[12] Toward the end of their stay, James used his money to pay for a French tutor and learn the language. Sally Hemings also was learning French.[9] There is no record of where she lived: it may have been with Jefferson and her brother in the Hôtel de Langeac on the Champs-Elysées, or at the convent where the girls Maria and Martha were schooled, the Abbaye de Panthemont. Whatever the weekday arrangements, Jefferson and his retinue spent weekends together at his villa.[13] Jefferson purchased some fine clothing for Hemings, which suggests that she accompanied Martha as a lady's maid to formal events.

Under French law, both Sally and James could have petitioned for their freedom, as the 1789 revolutionary constitution in France abolished slavery in principle. Hemings had the legal right to remain in France as a free person; if she returned to Virginia with Jefferson, it would be as a slave. According to her son's memoir, Hemings became pregnant by Jefferson in Paris and agreed to return with him to the United States after he promised to free her children when they came of age. Hemings' strong ties to her mother, extended family and siblings likely drew her back to Monticello.

In 1789, Sally and James Hemings returned to the United States with Jefferson. He was still only 46 years old and seven years a widower. As evidenced by Jefferson's father-in-law, John Wayles, wealthy Virginia widowers frequently took enslaved women as concubines. That Jefferson also would do so was not unusual for the time.[16]

According to Madison Hemings, Sally Hemings' first child died soon after her return from Paris. Those Jefferson records that have survived mutilation and purge note that Hemings had six children after her return to the US:[17]

Harriet Hemings (I) (October 5, 1795 - December 7, 1797)[18]
Beverley Hemings (possibly named William Beverley Hemings) (April 1, 1798 - after 1873)[18]
unnamed daughter (possibly named Thenia after Hemings' sister Thenia) (born in 1799 and died in infancy)[18]
Harriet Hemings (II) (May 22, 1801 - after 1863)[18]
Madison Hemings (possibly named James Madison Hemings) (January 19, 1805 – 1877)[18]
Eston Hemings (possibly named Thomas Eston Hemings) (May 21, 1808 – 1856)[18]

Jefferson recorded slave births in his Farm Book; unlike his practice in recording births of other slaves, he did not note the father of Hemings' children.[19]

Sally Hemings' documented duties at Monticello included being a nursemaid-companion, lady's maid, chambermaid, and seamstress. It is not known whether she was literate, and she left no known writings.[18] She was described as very fair, with "straight hair down her back".[11] Jefferson's grandson, Thomas Jefferson Randolph, described her as "light colored and decidedly good looking". As an adult she may have lived in a room in Monticello's "South Dependencies", a wing of the mansion which was accessible to the main house through a covered passageway.[20]

Hemings never married. As a slave, she could not have a marriage recognized under Virginia law, but many slaves at Monticello are known to have taken partners in common-law marriages (but no such marriage for Hemings is noted in the records). While Sally Hemings worked at Monticello, she had her children nearby. According to her son Madison, while young, the children "were permitted to stay about the 'great house', and only required to do such light work as going on errands".[9] At the age of 14, each of the children began their training: the brothers with the plantation's master in carpentry, and Harriet as a spinner and weaver. The three boys all learned to play the fiddle (Jefferson played the violin).[9]

In 1822 at the age of 24, Beverly "ran away" from Monticello and was not pursued. His sister Harriet Hemings, 21, followed in the same year. The overseer Edmund Bacon said that he gave her $50 and put her on a stagecoach to the North, presumably to join her brother.[21] In his memoir, Bacon said Harriet was "near white and very beautiful", and that people said Jefferson freed her because she was his daughter.[22] Madison Hemings said that Beverley and Harriet each entered white society in Washington, DC, according to their appearance, and each married well.[9]

Of the hundreds of slaves he owned, Jefferson formally freed only two slaves in his lifetime: Hemings' older brothers Robert, who had to buy his freedom, and James Hemings (who was required to train his brother Peter to get his freedom). He freed five slaves in his will - all males from the extended Hemings family, including Madison and Eston Hemings, his two "natural" children. Harriet was the only female slave he allowed to go free.[23] In addition to manumission for the Hemings men in his will, he petitioned the legislature to allow them to stay in the state. No documentation has been found for Sally Hemings' emancipation.[19][20]

Jefferson's married daughter Martha Randolph, who was Hemings' niece, withheld her from the auction and freed her by giving her "time" after Jefferson's death. This informal freedom allowed Hemings to live in Virginia, and she remained with her two youngest sons in nearby Charlottesville for the next nine years. In the Albemarle County 1833 census, all three were recorded as free white persons.Hemings lived to see a grandchild born in a house that her sons owned

Sarah Hemings