The 50-year-old man from Buckshaw Village suffered head injuries, concussion and multiple fractured ribs in the crash which happened at junction 28 at around 5.30pm, say police.
The man was freed from the car by emergency services before being taken to Royal Preston Hospital by air ambulance for further treatment.
Three other people were also reported injured in the accident, although police have confirmed that none of these injuries were life-threatening.
A 51-year-old man from St Helens and a 50-year-old man from Prescot, travelling in a Vauxhall Meriva, suffered whiplash and concussion and were taken by ambulance to hospital.
A 15-year-old boy from Chorley in another car was treated for whiplash injuries.
A police spokesperson added that the accident happened when a Volvo HGV travelling northbound in lane one left the carriageway towards the slip road.
As the vehicle exited the motorway it was involved in a collision with a number of cars before colliding with a Range Rover.
A number of vehicles including a Volvo S40, a Nissan Note, a Nissan Qashqai, a Renault Trafic, a Volkswagen Polo, a Ford Transit van and a Fiat Panda were also involved in the collision. Several motorists and passengers were treated at the scene for minor injuries.
Sgt Steve Hardman, of Lancashire Police’s Roads Policing Unit, said: “We are appealing for witnesses following a serious collision on the M6.
“A number of vehicles were involved close to Junction 28 with several people injured – one seriously.
“The incident caused significant delays in the area and we are grateful for the patience of motorists as emergency services worked at the scene.
“Anyone who saw the vehicles involved before the incident, or witnessed the collision, is urged to contact police.”
Anyone with information can call police on 101 quoting log reference 1146 of April 19.