The FAA said the pilot declared an emergency shortly after the plane had departed from John Wayne Airport.
The pilot and passenger- a man and a woman - were pulled from the fiery wreckage and taken to a hospital with "traumatic injuries", Orange County Fire Capt. Larry Kurtz told CBS.
KABC is reporting at least two people suffered critical injuries.
He said the crash happened under "unknown circumstances".
The plane caught fire and smoke from the crash could be seen for miles.
The Cessna 310 aircraft crash-landed just after 9:30 a.m. P.S.T. and burst into flames, reports indicate.
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Two people are injured after a small plane crashed Friday on the 405 freeway in Orange County, California near John Wayne Airport. Two people were on the six-seater Cessna 310.
The pickup truck's driver, Blackstone Hamilton, told KCBS-TV he initially though a large truck had slammed into the back of his auto and then saw flames quickly surrounding his vehicle.
LGB spokeswoman Stephanie Montuya-Morisky said it was not immediately known if any other flights would be redirected to Long Beach. They are both being treated by emergency responders.
The Federal Aviation Administration says the plane crashed just short of an airport runway.
John Wayne Airport tweeted that the nearby freeway has been closed in both directions "due to debris on the roadway".
In the aftermath of the crash, the airfield was closed to arrivals, but arrivals were resumed about 45 minutes afterward.