At around 6am, the A24 – between the Washington and Ashington roundabout – was closed for just over an hour after a van left the northbound carriageway and overturned near to the Orchard Fisheries and Spring Gardens, blocking the road.
A 29-year-old man and a 25-year-old man managed to get out of the van before the fire service arrived. They sustained arm and facial injuries and were taken to hospital by ambulance.
Sussex Police said at least seven vehicles were reported to have slid off the road in the same area.
A woman suffered neck injuries, not thought to be serious, after a silver Peugeot 207 car collided with a road sign east of the Bodyshop roundabout at 7.20am.
A man driving a black Renault Clio was left shocked when he was involved in a collision in the same area.
Motorists in Sussex are being advised to take extra care while driving in freezing conditions.