It happened just after 3:30 a.m. Saturday on the 500 block of Chester Pike in Norwood.
When firefighters arrived, they found flames shooting from the first floor of "Mattress Mart."
The mattress store was destroyed.
Two neighboring businesses suffered smoke and water damage.
There have been no reports of injuries.
Firefighters remained on the scene to put out any hotspots.
A cause of the fire is under investigation.