The A264 Five Oaks Road near Broadbridge Heath is currently shut both ways from Elmhurst Lane to Bashurst Hill.
Emergency services including an air ambulance rushed to the scene soon after 7.15am following the crash involving a car and a lorry.
A spokesperson for the South East Coast Ambulance Service said: “One person was assessed and treated at the scene before being taken in a serious condition to Royal Sussex County Hospital in Brighton.”
And a spokesperson for West Sussex Fire & Rescue Service said: "Joint Fire Control mobilised two fire engines from Billingshurst and Horsham to the scene, as well as a heavy rescue tender from Crawley.
"On arrival crews used hydraulic equipment to rescue one casualty from a vehicle and worked with colleagues from Sussex Police, South East Coast Ambulance Service and HEMS to make the area safe.
"The road will remain closed for some time and drivers are urged to avoid the area."
Meanwhile, a spokesperson for Sussex Police said: “Anyone who witnessed the incident or has any information or dashcam footage is asked to contact police online or call 101 quoting Operation Cureen.”
1. A264 crash
Scene of the crash between a car and a lorry on the A264 Five Oaks Road today Photo: Contributed
2. A264 crash
Fire crews say the road is likely to remain shut for some time Photo: Contributed