The crash between happened Friday afternoon when a pickup truck going north on Highway 63 pulled out to pass another vehicle, colliding with another pickup travelling south.
"There was a significant fire as a result of the impact," said Const. Christina Wilkins of Fort McMurray RCMP.
Passing motorists pulled a teenaged girl from the pickup that had been passing, say police. She was airlifted to a hospital in Edmonton, but died a few hours later from her injuries.
A young boy and a 34-year-old man were also airlifted to Edmonton hospitals. Their conditions are not known, and the identities and hometowns of the dead and injured have not been released.
It was snowing in the area at the time of the crash on the two-lane, undivided highway.
"There was some reduced visibility," Wilkins said, adding weather was still bad late Friday.
"We ask that people please be careful when they're travelling south of Fort McMurray, given the weather and the road conditions are still unfavourable."
Six people were in one of the pickups, while three were in the truck that had tried to pass.
Highway 63 reopened to traffic late Friday evening, after being closed for about eight hours due to the crash.
Two years ago, volunteer firefighters from Wandering River stopped responding to accidents on the highway because they found the work overwhelming.
In 2011, the provincial government and Athabasca County invested $1.3 million to hire more emergency responders to cover the route.
The highway is a busy route stretching north of Edmonton to Fort McMurray and north to the oilsands, where thousands of people work and tonnes of material and equipment moves daily.
Between 2001 and 2005, more than 1,000 crashes killed 25 people and injured 257 others on the highway.
In 2006, after years of public pressure, the Alberta government announced that it would twin a 240-kilometre stretch of the road. As of October 2009, 16 kilometres had been twinned.