The head-on collision happened at Clay Hill at 6.20pm and involved a silver Peugeot 206 travelling south and a silver Seat Ibiza travelling north. Both vehicles spun off the carriageway.
The driver of the Peugeot, a 47-year old Uckfield man, was taken to the Royal Sussex County Hospital, Brighton, with serious injuries. His condition is stable.
A woman who was a rear-seat passenger in the Seat was also taken to the RSCH with multiple injuries but following treatment was later discharged.
The Seat driver, a 38-year-old man from Littlehampton, and another passenger, a 12-year-old boy, were treated at the scene for minor injuries.
The affected section of the A26 was closed until 11pm while the incident was dealt with and the scene cleared of oil and debris.
Anyone who witnessed the crash or saw either vehicle being driven shortly before it occurred is asked to email email@example.com or phone 101, quoting Operation Normandy.