Authorities - including the FBI - are investigating the explosion of what were believed to be commercial-grade fireworks in Ontario, about 35 miles east of Los Angeles. About 50 firefighters still worked to douse the flames three hours after the initial blast.
Fireworks are illegal in Ontario, as they are in many California cities. Ontario Police Chief Mike Lorenz said officers have been called to the area in the past on reports of fireworks being set off.
Officials didn't immediately have information about where the cache in the explosion came from, or what was happening in the home where the blasts erupted.
"We don't know anything about the fireworks right now," Ontario Fire Chief Ray Gayk said.
The two people who were killed appeared to be inside or around the home, Gayk said.
Three other people had minor injuries and weren't hospitalized, Gayk said.
Others nearby were able to escape, authorities said.
Emergency crews responded around midday following reports of multiple blasts.
Steve Bailey, who lives nearby, said his whole house shook from the initial explosion. "It felt like something hit the roof, or a car crashed into the house," Bailey told our sister station ABC 7.
TV news footage showed at least one home burning and a shed and scattered debris on fire in a large backyard.
Oscar Vargas Ibarra, 17, who lives two houses from explosion site, told the Los Angeles Times that when the first blast hit, they grabbed their dog and bolted into the street.
Then there was a second, larger explosion and "that's when everyone ran, ran for their lives," he said.
The teenager said he knew people living at the destroyed home had fireworks, although he didn't know how many.
"They always pop them off, random sometimes, like at night shows or a holiday," he said.
Firefighters managed to free a horse on the property that was trapped against a fence near a pile of burning debris. Another horse managed to escape unharmed.
Several neighbors said windows at their homes were shattered by the initial blast.
Hours later, several smaller blasts went off, apparently from remaining fireworks, and a plume of smoke rose from the area.
People nearby were evacuated for at least the night or until the area is declared safe, fire officials said.
The Associated Press contributed to this report.