Police have closed Mythop Road in both directions after the crash, which involved a lorry and a car, near the junction with Church Road at around 10.15am.
The injured man, who has suffered serious injuries, is one of two casualties taken to hospital, say police.
Details on the second casualty have not been released at this stage.
Emergency services, including fire and ambulance crews, continue to work at the scene and drivers are asked to avoid the area until further notice.
A police spokesman said: “We were called at shortly after 10.15am today (Monday, March 7) to a report of serious collision on Mythop Road at Weeton between a car and a lorry.
" A man has been taken to hospital with serious injuries. Emergency services remain at the scene.
"We are asking the public to stay away from the area until further notice.”
The road closure is in place from Ream Hills Holiday Park and Weeton Village Hall, and is causing delays for those travelling between Blackpool and the Fylde.
A spokesman for Lancashire Fire and Rescue Service said: "Two fire engines from South Shore and Wesham supported by multiple Urban Search and Rescue Vehicles from Chorley Fire Station attended a road traffic collision on Mythop Road, Weeton.
"The incident involved a car and one lorry. Firefighters assisted medical personnel and worked to make the scene safe.
"Two casualties have been treated by North West Ambulance Service and have been conveyed to hospital. Crews were in attendance for one hour and thirty minutes."
North West Ambulance Service has been approached for further details.