The plane, a Bombardier Challenger 600, was trying to land on the highway when it collided with a car, according to the highway patrol. Pictures show black smoke rising from the burning plane on the highway.
It is not clear whether the two people who died were in the plane or the car that was hit.
The plane was according to Miami Herald En route from Ohio when she lost both engines. The intention was for the plane to land at Naples Airport in the city of the same name, which is located about 200 kilometers west of Miami.
The pilot reportedly informed air traffic control that he would not be able to reach the airport. That's why he decided to make an emergency landing on the highway.
Motorists stopped on the highway due to the fire burning on the road. Local authorities closed the highway for the next 24 hours.