St. Charles Police Chief Bill Eckles said the man and four other people were registered at the Downtown Motel at the time the fire was reported at 10:50 p.m.
KTTC TV identfied the man as Vincent Edward Wright.
Eckles said one of the remaining three made it out safely while the other two were not at the motel at the time.
He said the state fire marshal's office was called in to the investigate the cause of the blaze.
Eckles said the St. Charles Fire Department battled the fire without any assistance from other departments. They were on the scene until 3:30 a.m. but were called back an hour later when the fire rekindled.
When firefighters arrived on the scene flames could be seen coming from the roof and from a window. The fire caused extensive damage.
The American Red Cross of Winona, Wabasha, and Goodhue counties reports its volunteers provided canteen services at the scene for rescue workers as well as lodging for the people displaced by the fire.