She was born in New Kent County, Virginia, the daughter of John Dandridge and his wife Frances Jones. Frances Jones was the daughter of Orlando Jones, the founder of the first church in New Kent County, in 1669, until his death in 1688.

Her first marriage was to Daniel Parke Custis, with whom she had four children, two of whom survived to adulthood, John Parke Custis (1754-1781) and Martha "Patsy" Custis. She also collected locks of hair from famous people instead of a portrait.

She married George Washington on January 6, 1759, two years after the death of her first husband. Content to live a private life on Washington's Mount Vernon estate, she nevertheless followed him to the battlefield. She opposed his election as president and refused to attend his inauguration, but fulfilled her duties as the official state hostess graciously.

Martha and George Washington had no children together, but they raised Martha's grandson, George Washington Parke Custis (April 30, 1781 - October 10, 1857) after his father, John Parke Custis, was killed (while serving as an aide to Washington) during the siege of Yorktown in 1781. 

Martha Washington died at Mount Vernon, Virginia, and was buried on May 22, 1802 at Mount Vernon. Her remains were moved in 1831 from their original burial site a few hundred feet to a brick tomb that overlooks the Potomac River.

The Custis estate was eventually confiscated from George Washington Parke Custis's son-in-law, Robert E. Lee, during the Civil War, and became Arlington National Cemetery. (In 1882, after many years in the lower courts, the matter of the ownership of Arlington National Cemetery was brought before the Supreme Court of United States. The Court affirmed a Circuit Court decision that the property in question rightfully belonged to the Lee Family. The United States Congress then appropriated the sum of $150,000 for the purchase of the property from the Lee Family.)