The incident happened at around 4.30am, police added.
Police are now appealing for witnesses.
A Sussex Police spokesperson said: “Emergency services responded to a report of a single vehicle collision on the B2092 Crowhurst Road, St Leonards, at about 4.30am on Wednesday, September 11.
“A car had left the carriageway.
“Two passengers, a 28-year-old woman and a 32-year-old man were taken to hospital with serious injuries, where they remain.
“The driver, a 38-year-old man, was also injured and was taken to hospital, where he remains. Anyone with information about the collision is asked to report it to Sussex Police online or email [email protected] and quote Operation Elland.”
The section of road where the collision happened remains closed, with emergency services still at the scene.