The plane is on the southbound freeway near the MacArthur Boulevard exit.
The Cessna 310 aircraft landed on the freeway short of the runway at 9:35 a.m, the Santa Ana airport tweeted. The airfield is closed to arrivals, but departures are not affected.
Orange County Fire Authority Capt. Larry Kurtz said the plane had crashed and two people are being hospitalized with traumatic injuries.
Video recorded from a vehicle on the freeway showed black smoke billowing from the wreckage, with flames rising in the area of the center divider. Debris was all over the freeway, and bystanders could be seen stopping to help two people, at least one of whom was lying on the freeway pavement.
No other vehicles on the freeway were struck, Kurtz said.
A Federal Aviation Administration record for the plane’s tail number indicated it was a 1975 fixed-wing Cessna 310R registered to a Santa Ana company called Twin Props.