The collision at Pilfrey Bridge was reported to emergency services at around 11.45pm on Saturday.
A Nissan Skyline had broken down and pulled up, with it hazard and rear lights on, at the side of the road.
A blue Citroen C4 Picasso, travelling towards Scunthorpe, attempted to overtake the car and collided with a blue Mazda 2 travelling in the opposite direction.
The driver of the Mazda, believed to be from the Scunthorpe area, was taken to Hull Royal Infirmary with potentially life-threatening injuries.
The driver of the Citroen, who is from the Doncaster area, suffered less serious injuries and was taken to Scunthorpe General Hospital.
Passengers from both cars were taken to Hull Royal Infirmary with serious injuries.
Witnesses should call PC Sean Hutchinson at Humberside Police on 101, quoting log number 684 of July 18.