Traffic control measures, including multi-way temporary signals, will be in place from February 16 to February 20.
The temporary lights are likely to affect traffic flow along the busy route, particularly during peak travel times.
Portsmouth Road is one of the busiest roads in the city with regular queues to the Itchen Bridge during the rush hour.
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Drivers are being urged to plan ahead and allow extra time for their journeys while the works are underway.
Southern Water has said a traffic management system will remain in place for the duration of the works to avoid delays building where possible.
Road users are advised to follow signage in the area and take care when travelling through the temporary traffic controls.