The 84-year-old had been airlifted to Preston Royal Infirmary after the crash with a Tesco delivery van just before 4pm on Friday afternoon, but died a short time later.
He had been driving a blue Ford Fiesta, close to Whinney Mire Lane, on his way towards Settle while the delivery van was travelling in the opposite direction.
The driver of the Tesco van, a 62-year-old from Lancashire, escaped with slight injuries.
The A65 was closed in both directions for several hours while the emergency services worked at the scene.
Police said officers spoke to witnesses at the scene, but are now appealing for anyone with further information, or dash cam footage, to come forward.
Anyone with information is asked to call North Yorkshire Police on 101, asking for Andrew Ingram or the Major Collision Investigation Team quoting reference NYP-14092018-0295.