Police said the collision occurred on the Murray Valley Highway in Strathmerton, near the intersection of Stokes Road, about 12pm on Tuesday.
The van's driver, who is yet to be formally identified, died at the scene.
Two male officers, a first constable and a detective sergeant, suffered serious injuries.
Ambulance Victoria said one officer, aged in his 30s, was flown to the Alfred Hospital. Another, aged in his 60s, was taken to Shepparton Hospital.
Victoria Police said there was nothing to indicate the officers were pursuing the van at the time of the crash.
Eastern Region Assistant Commissioner Tony Langdon said he had the "really sad duty" of telling the officers' families.
"This is such a typical thing that occurs in country roads ... no one is immune from it. I've got two police members and their families to deal with," he told reporters in Wangaratta on Tuesday afternoon.
"I just ask people to take note of their driving."
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