The man was driving a blue Volkswagen Bora towards Harrogate when it was involved in a head-on collision with a black Ford C-max people carrier near Kex Gill Farm at 8.30am yesterday.
He was airlifted to Leeds General Infirmary with serious injuries.
The occupants of the C-max, two women and a boy from Harrogate, were taken to Harrogate District Hospital with non life-threatening injuries.
The road was closed for six hours following the collision.
Traffic Sergeant Andrew Morton said: “If you were in the area of the A59 at the time of the collision, I urge you to contact the police straight away as you may have vital information which could help this investigation.
“I am also keen to speak to anyone who may have seen either of the vehicles prior to the incident and ask them to get in touch as soon as possible.”
Anyone who can help should contact Chris Dundon at Harrogate police on 101 or email firstname.lastname@example.org. Please quote reference number 12140029210.