The incident occurred about 8.50am at the intersection of the Northern Hwy and Spiers Rd.
Victoria Police attended the scene, along with Advanced Life Support paramedic crews.
The driver of the car, who is yet to be formally identified, died at the scene.
A man in the passenger seat of the car was taken to the Echuca hospital in a stable condition, with no life-threatening injuries.
The driver of the truck stopped at the scene.
The circumstances surrounding the incident are yet to be established, and the investigation is ongoing.
The Northern Hwy, between Spiers Rd and Echuca-Mitiamo Rd, is closed to traffic in both directions due to the incident.
Road users are advised to allow extra time for their journeys and follow the direction of emergency services as investigations are carried out.
For traffic updates, visit tinyurl.com/rxvbtj7s
Anyone who witnessed the incident, with footage or information is urged to contact Crime Stoppers on 1800 333 000 or anonymously at crimestoppersvic.com.au
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