It happened at a home on Highway 90, about a mile outside of Monticello.
Fire crews said they found 55-year-old Ricky Fairchild in his bedroom and brought him outside.
The Wayne County Coroner said he was pronounced dead at the scene.
The coroner said heat and smoke inhalation killed Fairchild.
According to investigators, Fairchild had serious health issues and limited mobility, and was unable to leave the home as a result.
A cause of the fire has not been released.