The explosion happened before 11:30 a.m. at the Heritage Inn Sea World on 3333 Channel Way.
Helicopter video showed flames and smoke coming from the roof of the three-story motel. Fire crews and ambulances were parked in the street outside the building. Police were evacuating the building.
The victims, two men and woman, were taken by ambulance to the burn center at UCSD Medical Center, fire officials said. At least one of the victims had life-threatening injuries, the official said.
FOX 5 has a news team on the way to the scene. Additional updates will be posted as new details become available.