On August 5, 1818, Mary Hempstead Keeny married the Spanish fur trader, Captain Manuel Lisa, a widower with a son. The wedding was performed by the Presbyterian minister, Salmon Giddings, with Pierre Chouteau as a witness, at the home of Mary's parents. The Lisas lived in a home on Second Street in St. Louis, but because the fur trader was off on trading expeditions so much, the home was usually referred to as "Mrs. Lisa's house" or the "house of Aunt Manual" (as Mary had become affectionately known). 

In the spring of 1819, accompanying Manual on a trading mission, Mary became one of the first white woman to enter Nebraska - the Upper Missouri River area. They attended an Indian Council meeting at what is now Omaha, Nebraska. Mary became quite a celebrity there and was feted by both Indians and the Army . While in Nebraska, Mary learned of two children Manual had fathered with an Omahan woman, Mutain. The son remained with his Indian mother and died at an early age. After her father's death, the daughter, Rosalie, lived with Mrs. Lisa in St. Louis for a time.

Manual Lisa died on August 12, 1820, soon after returning from the Nebraska trip.  His fur company faltered under new ownership, increased competition, and over extension and debt. Because of this and proscriptive laws pertaining to widows' rights, Mary was left with little money. She remained a widow for the rest of her long life. She is remembered for caring for family, friends and Indians alike, earning her nickname of Aunt Manual. She died on September 3, 1869, in Galena, Illinois, where she had gone to help care for her brother. Her remains were brought back to St. Louis where she was buried next to Manual Lisa in the family burial ground on the Hempstead Farm.