The crash happened this afternoon on the Western Freeway in Derrimut, to the west of the city.
A truck collided into the rear of a Toyota Corolla on the Robinsons Road off-ramp about 1.30pm.
The Toyota Corolla then crashed into the back of a Volkswagen Golf.
The female driver and a one-year-old passenger were taken to hospital with injuries.
Another passenger inside the Corolla was trapped for some time before emergency services were able to remove them.
He was taken to hospital with serious lower-body injuries.
The sole male driver of the Volkswagen was also taken to hospital for precaution, Victoria Police said.
The driver of the truck was uninjured and taken to hospital for blood tests.
Melton Highway Patrol officers are investigating the cause of the crash.
Traffic is backlogged several kilometres and all outbound lanes are closed.
Any witnesses or anyone with dashcam footage is urged to contact Crime Stoppers on 1800 333 000.