Following the premature death of their father John Parke Custis in 1781, Nelly and her brother, George Washington Parke Custis, were placed under the guardianship of the Washingtons and grew up at Mount Vernon, although they visited their mother, stepfather David Stuart and older sisters at Abington and later at Dr. Stuart's estates in Fairfax County.

On February 22, 1799, Nelly Custis married George Washington's nephew, the widower Lawrence Lewis of Fredericksburg, Virginia.

[2][3] The Lewises had eight children, four of whom lived to adulthood: Upon her marriage, Nelly Lewis inherited about 80 slaves from her father's estate.

Her grandfather Daniel Parke Custis's estate was liquidated following Martha Washington's death in 1802, and Nelly Lewis inherited about thirty-five "dower" slaves from Mount Vernon.

Following the death of Eleanor Calvert in 1811, the John Parke Custis estate was liquidated, and Nelly Lewis inherited approximately forty additional slaves.