Federal Aviation Administration spokesman Ian Gregor said the plane went down about 12:40 p.m.
The San Bernardino County Sheriff's Department said three passengers were killed and that there were no survivors.
The plane was en route from John Wayne Airport in Santa Ana and headed for Henderson Executive Airport near Las Vegas. It crashed near Daggett, about 10 miles east of Barstow and 120 miles northeast of Los Angeles.
Gregor said the plane is believed to be a Cessna 210.
The cause of the crash is under investigation.
The Associated Press contributed to this report.