The crash happened about 3.30am on the Western Highway near Beaufort.

Rural Ambulance Victoria spokesman John Mullen described both drivers as being in serious but stable conditions.

A 34-year-old male driver received facial and lower leg injuries, while the other driver, a 60-year-old man, received facial, head, chest and leg injuries.

Both were taken to Ballarat Health Services Base Hospital.

Crews are working to clear the scene, but the highway remains blocked between the Learmonth Road overpass at Mitchell Park and Ararat. 

Vehicles are being detoured via the Sunraysia Highway and Pyreness Highway via Avoca.