The crash happened Tuesday evening on Highway 2A north of Wetaskiwin.
RCMP say a southbound vehicle crossed into the northbound lane, colliding first with a pickup truck and then with a van.
The driver of the first vehicle died at the scene, while a passenger and the occupants of the truck and the van were taken to hospital by ambulance.
There is no word on their conditions.
The name of the person who died has not been released and police are still trying to determine whether alcohol was a factor in the crash.