Police were called out to the A170 between Helmsley and Sutton Bank at around 7am today.
The fire and ambulance services also attended the incident, which involved a Citroen Berlingo and a Toyota Hi-Lux.
A North Yorkshire Police spokesman said: "Sadly, one man – believed to be the driver of the Citroen – was pronounced dead at the scene.
"The other driver has been taken to hospital and the extent of his injuries is not yet clear."
The road was shut to allow emergency services to carry out their work at the scene.
It remains closed and drivers are being advised to use alternative routes.
The force said it was not yet in a position to release the identity of the man who died.
Officers now want to hear from anyone who witnessed the collision, saw the vehicles in the moments before it happened or has any dashcam footage that could help the investigation.
Email [email protected].pnn.police.uk or call 101, select option 2 and ask for Emma Drummond.
Please quote reference NYP-22022019-0062 when sharing information.