The fire erupted shortly after 5 p.m. in a rental home attached to a main house in the small unincorporated community of Monte Nido, between Malibu and Calabasas.
Hazmat and narcotics teams planned to enter the building to determine if a drug lab was involved.
Three men in their early 20s were hospitalized with moderate to serious burns, more than 20 to 30 percent of their bodies.
A man who was visiting a few doors away saw the badly burned victims.
"They were more in a state of shock, I'd say," said Bryan Campbell, a witness. "They just kind of had that empty look."
Firefighters managed to put out the blaze in eight minutes.