The man, from Liversedge, was driving a black Renault Megane Coupe from junction 27 of the M62 towards Leeds city centre when the incident happened.
The car left the carriageway and overturned before colliding with a large motorway sign at 3.40am.
The car was left badly damaged and the driver was taken to Leeds General Infirmary.
Another man, who had been a passenger in the vehicle, was also injured and was taken to hospital but his injuries were less serious, police said.
Anyone who witnessed the collision or who saw the Renault in the area beforehand is asked to contact PC 571 Richard Whiteley of the Safer Roads and Neighbourhood Support East team via 101 quoting log number 145 of March 12.