Three people have died following a serious multi-vehicle crash on the Western Highway at Ledcourt in Victoria's north-west.

The collision occurred on Sunday evening near Mount Drummond Road, with emergency services responding to the scene at approximately 6:45pm. Police said two cars were involved in an initial collision, after which one of the vehicles struck the side of a truck before colliding with another car.

Two people travelling in the third vehicle died at the scene. Their identities had not yet been formally confirmed when the latest police information was released.

A 14-year-old girl who was travelling in another vehicle was flown to hospital following the crash but later died from her injuries. Her death increased the number of fatalities from the collision to three.

Several other people were injured. A 17-year-old learner driver was taken to hospital with upper-body injuries and was reported to be in a stable condition. An 11-year-old girl who was also travelling in the vehicle suffered upper-body injuries and was in a critical condition. A 43-year-old woman who was another passenger was not injured.

The truck driver involved in the collision was also not injured and remained at the scene.

The crash caused major disruption on the Western Highway, with the road closed in both directions while police and investigators examined the scene. The road was reopened on Monday morning after the investigation work had progressed.

Victoria Police's Major Collision Investigation Unit is investigating the circumstances surrounding the crash. Investigators are examining possible factors that may have contributed to the collision, including fatigue, distraction and speed. Police have not reached a conclusion about the cause.

The incident occurred as people were travelling during the long weekend period, when roads in regional Victoria can experience increased traffic. Police have appealed for anyone who witnessed the crash, or who may have relevant CCTV or dashcam footage, to contact Crime Stoppers.

The deaths have added to concerns about serious road incidents on regional highways, where high-speed traffic and long travel distances can increase the consequences of crashes.

Authorities have urged motorists to take care on the roads, particularly during busy travel periods, and to remain attentive and well-rested.

The investigation remains ongoing, and police are continuing to establish the precise sequence of events that led to the fatal collision.