The car was travelling outbound on the freeway near Williamstown Road at Spotswood when it collided with the truck just after 10.30am on Tuesday, police say.
Fire crews arrived to find a truck had rolled over and worked to contain smoke coming from the vehicles, Fire Rescue Victoria says.Â
Callers to Melbourne radio 3AW reported a silver sedan crossing four lanes of the bridge at speed.
"It was like a bullet," one caller said.
The car's driver, a 21-year-old Wyndham Vale man, was taken to hospital where he remains in a stable condition.
One of his passengers was taken to Royal Melbourne Hospital with critical injuries.
The Ford Falcon XR6 sedan involved in the accident was carrying false licence plates, police said.
Three other passengers in the vehicle, males aged in their 20s, were arrested at the scene after it was suspected of being stolen.
They have since been released pending further enquiries.
Two men in the truck, aged in their 20s and 50s, were not injured and assessed by paramedics at the scene.
The bridge was blocked off in both directions soon after the crash, and all lanes have since reopened.
The exact circumstances surrounding the collision are yet to be determined and the investigation continues.
Police have called on anyone with dashcam footage to come forward.