North Yorkshire Police are appealing for witnesses to the fatal crash near Harden Bridge, which happened at 2.50pm on Friday.
It involved a blue Renault Clio that was travelling south along the A65 towards Settle from Ingleton, and an articulated lorry - a blue curtain-sider with a white tractor unit - which was heading in the opposite direction.
The 40-year-old man driving the Clio tragically died at the scene. Police were not in a position to release his identity but confirmed he is from the Derby area.
The driver of the lorry, a 31-year-old woman from Kendal in Cumbria, did not require hospital treatment.
Diversions remained in place until 9.30pm on Friday to allow for the police examination of the crash scene and for the vehicles to be recovered.
Investigating officers are appealing for anyone who saw either vehicle prior to or at the time of the collision to contact them as soon as possible.
Please contact North Yorkshire Police on 101, select option 2, and ask for Pete Stringer or Road Policing Group Skipton, or email firstname.lastname@example.org Please quote reference 12140129286 when providing details about this incident.