The blaze was reported at 7:44 a.m. at the Nash Hotel, located at 2045 University Ave., interim fire Chief Gil Dong said.
The fire was controlled at 8:25 a.m.
Everyone was evacuated from the building, and at least two people are being medically evaluated at the scene, Dong said.
Dong said it is unclear where hotel guests will reside because the building is now uninhabitable.
Crews are still at the scene.