The collision occurred about 2.30pm when a B-double truck carrying grain struck three cars, including one towing a boat, on the Calder Freeway in Diggers Rest.
Firefighters have been working to remove two people from one of the cars.
Five people have been injured, according to Ambulance Victoria, with a child taken to the Royal Children’s Hospital and a person taken to the Royal Melbourne Hospital.
An air ambulance helicopter is on scene, along with paramedics, police and firefighters.
The freeway is blocked inbound.