Contractors from Highways England are resurfacing a 1.5 mile stretch of the westbound carriageway between the Scarborough Road junction for Norton and the A169 junction for Pickering.
The westbound carriageway will be closed overnight, Monday to Friday, during the work which will be carried out between 8pm and 6am from Tuesday 1 December until Friday 8 January.
Highways England project manager Martin Barnes said:
When complete, this project will provide drivers with smoother and safer journeys along the A64.
The work will be carried out overnight when traffic levels are at their lowest to keep disruption to a minimum.
Westbound traffic will be diverted off the exit slip road to the B1248 Scarborough Road before turning right on the B1257 at Castlegate. Traffic will then re-join the A64 at the junction with the A169, Pickering Interchange.
Members of the public should contact the Highways England customer contact centre on 0300 123 5000.
Journalists should contact the Highways England press office on 0844 693 1448 and use the menu to speak to the most appropriate press officer.