A twin-engine Cessna 414A crashed in Yorba Linda, in Orange County, just after taking off from the Fullerton Municipal Airport, according to the Federal Aviation Administration.
It is still unclear whether or not the pilot is one of the deceased.
Video posted on Twitter showed panicked residents running to the house as it became engulfed in flames and dark smoke.
The Cessna 414A was said to have taken off from a nearby municipal airport shortly before the crash.
The crash occurred in Yorba Linda, the Orange County Fire Authority said on Twitter.
Seventy-two fire fighters attended the scene alongside local police, with the investigation into the crash still ongoing.
Firefighters respond to the scene of a plane crash at a home in Yorba Linda, Calif., Feb. 3, 2019.
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No other information was immediately available.
At least two people were killed, and two others were taken to a local hospital, according to OCFA.
The number of people on board the plane is unknown at this time.
Authorities say a small plane has crashed in a suburban Southern California neighborhood and has ignited a fire that burned two houses.
The main body of the twin-engine plane was found in the backyard of another home not far from the burned house.
Aerial footage taken from news helicopters show plane parts, including side panels and a propeller, scattered on rooftops and driveways near the burned house.