Five people were travelling in a car that crashed into a ute on Pine Lodge North Road, near Cosgrove-Lemnos Road, in Pine Lodge near Shepparton about 4.45pm, according to police.
The force of the crash pushed the car into a nearby paddock.
All four passengers in the car, who are yet to be formally identified, have been killed and the driver left seriously injured.
The driver has been airlifted to Goulburn Valley Health Hospital.
The driver of the ute was not seriously injured and stopped to help at the scene.
The cause of the collision is yet to be determined.
Anyone who witnessed the collision, has dashcam footage or information is urged to contact police.