Anna was born at her father's estate Solitude, just outside Morristown, New Jersey (present day Wheatsheaf Farms subdivision off Sussex Avenue in Morris Township, New Jersey) on July 25, 1775, to Judge John Cleves Symmes and Anna Tuthill Symmes of Long Island. Her father was a Chief Justice of the New Jersey Supreme Court and later became a prominent landowner in southwestern Ohio. When her mother died in 1776 her father disguised himself as a British soldier to carry Anna on horseback through the British lines to her grandparents on Long Island, who cared for her during the war. Her father was also deputy to the Provincial Congress of New Jersey (1775-1776), the Chairman of the Sussex County Committee of Safety during the Revolution, and a New Jersey delegate to the Continental Congress (1785-1786).
She grew up on Long Island, receiving an unusually broad education for a woman of the times. She attended Clinton Academy in East Hampton on Long Island, and the private school of Isabella Graham in New York City.
In 1794, Anna went with her father and new stepmother, Susannah Livingston, daughter of the Governor of New Jersey William Livingston, into the Ohio wilderness, where they settled at North Bend, Ohio. While visiting relatives in Lexington, Kentucky in the spring of 1795, she met Lieutenant William Henry Harrison, in town on military business. Harrison was stationed at nearby Fort Washington. Anna's father thoroughly disapproved of Harrison, largely because he wanted to spare his daughter the hardships of army camp life. Despite his decree that the two stop seeing each other, the courtship flourished behind his back.
While her father was away on business in Cincinnati, the couple eloped and married on November 22, 1795 at the home of Dr. Stephen Wood, treasurer of the Northwest Territory, at North Bend. The couple honeymooned at Fort Washington, as Harrison was still on duty. Two weeks later, at a farewell dinner for General "Mad" Anthony Wayne, Symmes confronted his new son-in-law for the first time since their wedding. Addressing Harrison sternly, Symmes demanded to know how he intended to support a family with Anna. Harrison responded "by my sword, and my own right arm, sir." Not until his son-in-law had achieved fame on the battlefield did Symmes come to accept him.
The couple apparently had a happy marriage despite the succession of tragedies in the untimely deaths of five of their grown children.
Harrison won fame as an Indian fighter and hero of the War of 1812, but he spent much of his life in a civilian career. His service in Congress as territorial delegate from Ohio gave Anna and their children a chance to visit his family at Berkeley, their plantation on the James River. Her third child was born on that trip, at Richmond in September 1800. Harrison's appointment as governor of Indiana Territory took them even farther into the wilderness; he built a handsome house at Vincennes, Indiana that blended fortress and plantation mansion.
Facing war in 1812, the family moved to the farm at North Bend. There, upon hearing news of her husband's landslide electoral victory in 1840, home-loving Anna said simply: "I wish that my husband's friends had left him where he is, happy and contented in retirement."