Police said the three people, who are yet to be formally identified, died at the scene.
Three others have been taken to hospital with non-life-threatening injuries.
The driver of the truck was uninjured and stopped at the scene, police said.
The exact cause of the collision is yet to be determined at this stage, according to police.
Major Collision Investigation Unit detectives are en route to the scene.
Anyone who witnessed the collision, or has dashcam footage or information is urged to contact Crime Stoppers on 1800 333 000 or submit a confidential report online at www.crimestoppersvic.com.au.
4.09PM UPDATE: The Murray Valley Hwy is closed between Cobram and Strathmerton.
Drivers are to divert via the Benalla-Tocumwal Rd, Nathalia-Katamatite Rd and Goulburn Valley Hwy.
EARLIER: Emergency services are on the scene of a bad vehicle crash at Strathmerton on Thursday, April 20.
Police said the crash on the corner of Murray Valley Hwy and Labuan Rd happened at about 2.30pm.
It is unclear how many vehicles are involved or the conditions of their occupants at this stage.
Parts of the road are closed.
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