The collision happened at about 11.10pm yesterday (Wednesday), on the eastbound carriageway of the motorway near Goole.
The brown Vauxhall Insignia left the road and collided with a bridge support of an overhead on the A614, a spokesman for Humberside Police said.
A 23-year-old man from Leeds, who was driving the car, suffered serious and potentially life-threatening injuries.
He was today (Thursday) being treated at Hull Royal Infirmary.
Police have issued an appeal for any witnesses to the collision to get in touch, as officers try to establish the circumstances surrounding the crash.
Anyone with information is asked to call police via 101, quoting log number 611 of June 27.