Two of the injured are in critical condition. Initial reports say a firefighter injured his knee and was taken to a nearby hospital.
The fire broke out at the Southwest Inn at about 12:10 p.m. along the inbound Southwest Freeway near Hornwood, according to the Houston Fire Department. The flames also burned a sports bar and disco.
The blaze sent black smoke billowing over the freeway, causing traffic to slow in the area.
Initial reports indicate police closed several entrance ramps to the freeway near the scene.
It was unclear what sparked the blaze.