Emergency services were called to several reports a car had driven down a cliff on Euroa-Mansfield Road, near Ridge Road, Gooram about 11pm.
Three male occupants were rescued from the vehicle.
The driver and one of the passengers were taken to hospital with life-threatening injuries.
The other male passenger, who is yet to be formally identified, was airlifted to hospital in a critical condition. He was later pronounced deceased.
Anyone who witnessed the collision or has dashcam/CCTV footage is urged to contact Crime Stoppers 1800 333 000 or www.crimestoppersvic.com.au.