Eight engines and 40 firefighters were called out to the Hampton by Hilton Hotel in Corby at about 15:45 GMT on Saturday.
Northamptonshire Fire Service said everyone was accounted for, and that four people were treated at the scene after breathing in smoke.
The service said all the guests had been relocated and crews had returned to base by Sunday morning.
The cause of the fire, at the Rockingham Leisure Park on Princewood Road, is being investigated.
The hotel's duty manager said she was unable to provide any further details about the fire, but confirmed the hotel was closed.
A hotel had to be evacuated after a fire that affected three floors.