The twin-engine plane came apart and caught fire mid-flight, witnesses told local media, before crashing in Yorba Linda, a suburb of Los Angeles.
The flight went awry just minutes after taking off from a local airport, some 20 miles (32km) south-east of the city.
The victims have not yet been named. Fire officials say two people were treated in hospital for burns.
Local residents described a shrill whistling sound before an explosion set the two-storey home on fire at 13:45 (21:45 GMT) on Sunday.
The pilot was the Cessna 414A's only occupant, and a source told the Los Angeles Times the man had flown frequently out of the Fullerton Municipal Airport.
Those killed in the home were two males and two females, Orange County officials said at a news conference..