The home was built by William Lenoir beginning in 1788 and was finished in 1792. When the house was originally constructed there were five outbuildings built within a 75 yard radius, a smokehouse, loom house, dairy, summer kitchen and corn crib. Today the smokehouse is the only other original building still standing.
Lenoir's home was named for the original Fort Defiance built prior to the American Revolution. By the time construction of the house started the fort was abandoned. Today nothing remains of the frontier fort.
The home was altered by the family over the years with additions and moving parts of the home around to suit the family's needs. When the home underwent restoration, the additions were removed and parts were reattached to bring the house back to its 1792 appearance.
During the history of the house, parts of it were used as a lumber office and a US Post Office. The Lenoir family lived in the house from 1792 until 1961.
The home reopened in 1976 operated by a 501(c)3 nonprofit, Fort Defiance, Inc., which oversees the operation of the historic home and grounds. The organization relies upon grants, paid tours, and memberships for continued operations.