The freeway is closed in both directions near the transit hub.
The plane, described by the airport and FAA as a twin-engine Cessna 310, crashed around 9:30 a.m., Orange County Fire Capt. Larry Kurtz said.
The Cessna 310 with two people on board crashed with its nose down and landed on the southbound lanes.
The aircraft, which appeared to be rapidly losing power, is seen leveling out slightly before hitting the ground and bursting into flames about 300m from a runway at John Wayne Airport in Santa Ana.
Two people aboard the plane suffered traumatic injuries and were in unknown condition as of early Friday afternoon local time, according to fire authorities.
The FAA said the pilot declared an emergency shortly after the plane had departed from John Wayne Airport. It is unclear if the injured parties were on the plane or drivers on the freeway.
It's incredible more people were not injured or killed, really. The extent of the injuries were not known.
The airport is located next to the interstate, and the plane crashed in the southbound lane not far from of the runway it was trying to reach.
"We take them as needed", she said. The airfield is closed to arrival.
The investigation is expected to cause major traffic flow problems for the already-busy Fourth of July weekend.