The fire started just before 10pm Saturday on the 10th floor of the Omni Hotel on Riverway at South Post Oak Lane.
The fire was contained to one room, but guests throughout the hotel smelled smoke.
The fire department evacuated the 10th and 11th floors.
Guests rushed to get out of the building and some managed to come outside with some of their belongings.
One man whose room was right next to the fire says he only had enough time to get his family.
"Our kids were in a separate room and we came down the steps carrying all of our grandkids," Greg Burleson said. "We didn't actually see smoke when we were leaving there, but they told us to evacuate immediately."
Firefighters made a fast attack and were able to extinguish the blaze within about 30 minutes.
The extent of the damage was unknown late Saturday.
One guest was taken to the hospital with signs of smoke inhalation.
Arson investigators are looking into the cause of the fire.