Police believe a truck and three cars were involved in the collision in the west-bound lanes of the Princes Freeway near the Bona Vista Road exit in Darnum about 8.40am.
A front seat passenger of a bronze Jeep, a 30-year-old Warragul woman, died at the scene.
The driver of that car, a 32-year-old Warragul woman, was airlifted to the Royal Melbourne Hospital with life-threatening-injuries.
The backseat passenger, a 14-year-old Warragul girl, was airlifted to the Royal Children’s Hospital with serious injuries.
The occupants of a white Mitsubishi, a 53-year-old Yarragon man and a teenage boy from Yarragon, were treated by paramedics.
The sole driver of a silver Mazda, a 21-year-old Tooradin woman, was transported to hospital with non-life-threatening injuries.
The truck driver, a 61-year-old Trafalgar man, is assisting police investigating the crash.
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Victoria Police Detective Sergeant Darryl Out described the scene as “horrific”.
“Everybody that would have seen that would have been just absolutely devastated by it,” he said.
“The 14-year-old child was very, very traumatised by it.”
About 9.45am, an hour after the first crash, a second collision occurred on the outbound lanes of the Princes Freeway at Nilma, just hundreds of metres away.
Two people were taken to Latrobe Regional Hospital.
The crashes come after a horror weekend on Victorian roads.
Two people were killed after a car hit a powerpole in Thomastown yesterday morning.