Emergency services were called to a crash between a truck and a car on the Cobb Hwy, near the Barmah Rd intersection, between Moama and Mathoura at 8.30am.
The driver and passenger of the car, both believed to be aged in their 80s, were both flown to Melbourne hospitals in critical conditions, according to police.
The driver, a woman, was flown to The Alfred hospital, while her male passenger was taken to Royal Melbourne Hospital.
The truck driver, a man aged 56, was treated for minor injuries before being taken to Deniliquin hospital for testing.
Local holiday makers and visitors planning to travel on the Cobb Hwy between Moama and Mathoura today will have to change their travel route following the collision near the Barmah Rd turn-off.
Murray River Council has advised drivers that due to a vehicle incident at the Cobb Hwy and Barmah Rd intersection, the Cobb Hwy is closed for traffic from Mathoura to the Tataila Rd intersection.
Barmah Rd is also closed from the Barmah bridge.
Cobb Hwy detour is Tataila Rd, 24 Lane, Hillside Rd, Thyra Rd, Bunnaloo Rd to Cobb Hwy at Mathoura.
This diversion is suitable for all vehicles up to 26m B-doubles and adds about 30 minutes of extra travel time.
Barmah Rd detour is through Victoria.
Motorists are advised to avoid the area and follow the detour signage.
For the latest traffic information on this incident, visit https://www.livetraffic.com/incident-details/231722
It is understood ongoing police investigations are expected to take some time.
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