Police said it happened on Hofstetter Road in the town of Blandford-Bleinheim, southwest of Kitchener, shortly after 1pm on Monday.
Ontario Provincial Police Const. Ed Sandchuk said a northbound SUV and a southbound vehicle collided for unknown reasons.
The driver of the southbound vehicle suffered life-threatening injuries and was taken to a local hospital, where he was pronounced dead, Sanchuk said.
Meanwhile, the occupants of the SUV – a man and three children – were also injured in the collision.
The man and two of the children were taken to a hospital with non-life-threatening injuries, Sandchuk said, adding that the third child was airlifted to a hospital in non-life-threatening condition.
The cause of the crash is unknown.
Sanchuk said police are looking to speak to the driver of another vehicle, who may have been in the area at the time of the crash.
Police closed Hoffstead Road between Township Road 14 and Oxford Waterloo Road.
Sanchuk said the closure is expected to last until late Monday night while police investigate the circumstances surrounding the crash.
