Victoria Police said an unmarked police car and ute collided on Kulkyne Way near Forbes Road in Red Cliffs about 10pm yesterday.
A third car was also involved in the crash.
A female senior constable and the male driver of the ute died at the scene.
Her colleague, a male leading senior constable, was airlifted to hospital in a critical condition.
Two young children, who were passengers in the ute, were taken to hospital for treatment for non-life-threatening injuries.
The driver of the third car and a child suffered minor injuries and were also taken to hospital.
Police are trying to determine how the crash happened.
“Major Collision Investigation Unit detectives are investigating and are travelling to the collision site,” police said in a statement.
It is expected Kulkyne Way will be closed today while detectives process the scene.
Anyone who saw the crash, or who has dashcam footage, is urged to call Crime Stoppers on 1800 333 000.