At 11.50am this morning, a lorry had been shedding a tank of oil onto the road from the A23 onto the A27.
The road is closed eastbound on the A27, between A23 north of Brighton and the Southerham roundabout junction on the A26 in Lewes.
The spillage has caused drivers to spin out of control.
A Mini overturned onto its roof at Falmer, near the Amex Stadium, due to the oil spillage.
A woman suffered minor injuries.
A spokesman for Sussex Police said the Highways Agency are currently clearing up the diesel spillage.
It is not known when the roads will reopen.
He said: “It has caused major delays and chaos for drivers on the bank holiday weekend.
“Everyone is being redirected to Brighton.”
The westbound carriageway of the A27 is to remain open.