It happened at 1pm on the A658 (Harrogate Road) between Huby and Pool-in-Wharfedale.
A silver Honda Civic and a green Mercedes HGV collided between Castley Lane and Riffa Business Park.
The driver of the Honda was rushed to hospital with serious injuries.
The HGV driver was not injured.
North Yorkshire Police have closed Harrogate Road at the scene of the crash and a long diversion is in place.
The Flying Tiger 747 and Connexions X52 bus services are likely to be disrupted due to the diversion.
A spokesperson for North Yorkshire Police said: "The road is likely to be closed for some time whilst police examine the scene and officers would like to thank motorists for their patience as the road closure involves a long diversion at a busy time of day.
"We are appealing for witnesses or anyone who may have dash-cam footage of the incident."
Quote North Yorkshire Police reference number 12200004197.