West Street is being closed for three weeks after investigations revealed part of the road needs rebuilding and resurfacing.
From October 23, the road will close from the Orchard Street roundabout to Tower Street.
The section will be closed to cars and other light traffic, but buses and large delivery vehicles will still be given access with no other suitable route through the city centre possible.
Parking bays will be suspended, and West Sussex County Council says it is liaising with residents and businesses to try to minimise disruption.
Cabinet member for highways and infrastructure, Bob Lanzer, said: “Unfortunately there will be inconvenience, for which we apologise, but we will do all we can to minimise the impact of the works.”
Pedestrians will still be able to use the pavements, while cars will be diverted via Orchard Street to North Walls.
Traders in South Street suffered months of misery when the road was dug up for resurfacing and gas works three times from January 2016 to March this year, leaving many furious.
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