The head-on collision happened at 6.35am today on Skipton Road between Claro Road and Westmorland Street.
It involved a red Ford Transit flatbed lorry, which was travelling towards Westmorland Street, and a dark grey Peugeot 3008 travelling in the opposite direction.
The lorry driver, a 49-year-old man from Wetherby, was taken to Harrogate District Hospital.
He is in a serious but stable condition, North Yorkshire Police said.
The 60-year-old Harrogate man driving the car was also taken to hospital with slight injuries.
A spokesman said: "Police are investigating the collision, including the possibility that the lorry driver may have suffered a medical episode at the wheel, immediately prior to it."
Anybody who witnessed the collision, or either vehicle involved prior to it, is asked to contact North Yorkshire Police.
Please call 101 and quote reference 12180188471 to pass on information.