The fire started around 9.30pm on the ground floor. Hotel staff members tried to control the fire with extinguishers but the blaze spread to the floors above. More than 20 fire trucks were sent to the scene to battle the flames, which spread rapidly.
It took more than two hours to control the fire, which had by then spread to the fifth floor of the 11-story hotel.
The Kaen Inn was built 45 years ago and was the first five-star hotel in the province. The hotel has around 160 rooms.
Guests and staff were all evacuated. About 10 people received minor injuries - smoke inhilation and slipping and falling during the evacuation.
Theerasak Teekayuphan, mayor of Khon Kaen municipality, said a witness had heard what seemed like an explosion from the lift in front of the kitchen on the ground floor.
The cause of fire had not yet been identified. Police investigators suspect it was started by an electrical fault.
An inspection on Monday morning shown that a total of 20 rooms were burnt by the fire. Guest were allowed to check and recover property left in their rooms.
The hotel has closed its doors.