It is believed the truck driver lost control before crashing into two parked trucks on the Hume Freeway near Wangaratta South just before 5am.
The driver, who is yet to be identified, died at the scene.
The two occupants of the parked trucks were sleeping at the time and were not injured.
Police are still investigating the circumstances around the crash.
Anyone who witnessed the incident or has dashcam or CCTV footage is urged to contact police or Crime Stoppers on 1800 333 000.