Resurfacing and reconstruction work on Lindum Hill is set to begin this week for nine days.
The A15 will be closed between 7am and 9pm, starting October 22. The southbound road will be closed throughout, being entirely closed from 29 to 30 October.
Due to severe weather conditions last year, the road has deteriorated, especially at the top of the hill, the County Council said.
Diversions and temporary traffic lights will be put in place during the work, and the council advises people add extra time onto their journey.
Project Leader, Tim Mawson, said: “We recognise that this is a key route through the city which is why the improvements are taking place during the school holidays to keep disruption to a minimum.”
Bus services, local residents and the emergency services have also been informed that the work is taking place.