Investigators suspected guests at the Heritage Inn in the city's Midway district were cooking a batch of methamphetamine or some other illicit drug in a second-floor room when the blast occurred late Wednesday morning, police said.
The explosion blew out a wall, sent window glass flying and sparked a fire that spread to the third story and the roof of the motel, firefighters told KNSD-TV, San Diego.
Witnesses said one victim was burned from head to foot. All three of the injured were transported by ambulance to hospitals.
The motel is located approximately 1 mile from Sea World.