The Old Kent Road was closed in both directions between Trafalgar Avenue and St James's Road on Friday morning after a water main burst in the middle of the night.
Police are advising motorists to avoid the Old Kent Road.
Officers were alerted to the burst main – near the Asda store and McDonald's restaurant – at about 3.45am on Friday.
"We are advised by Thames Water that it may be some days before the main is repaired and then the road repaired," says a Metropolitan Police spokesman.
"Diversions are in place, and motorists who normally use this route are strongly encouraged to seek alternatives if at all possible, in an effort to minimise congestion."
Buses were diverted via Dunton Road and Southwark Park Road.
Update Friday PM: the road has reopened westbound but the eastbound carriageway remains closed.