A red Vauxhall Astra collided with a Volvo HGV on the A92 Kirkcaldy to Dundee road, between the Redhouse and Bankhead roundabouts, at about 5.20pm.
The vehicle ended up wedged beneath the articulated lorry.
The 41-year-old man behind the wheel of the Vauxhall had to be freed by firefighters following the crash and was taken to Ninewells Hospital.
A police spokesman said the driver has suffered life-threatening injuries.
Sergeant Ewan Pearce, from the Glenrothes Road Policing station, added: “We are asking for anyone who witnessed the crash, or was driving through the area around the time, to come forward with any information they have, which could help our inquiries.
“Anyone with information can contact Police Scotland on 101, quoting incident 2547 of November 20.”
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