The improvements - which include resurfacing work and replacement of white road markings and studs - will be carried out in several phases at a cost of £5m.
The first phase, which will see white lining carried on the A66 starting at the Cumbrian Boarder, will start on Monday and will continue until early September.
All the work will be done overnight between 8pm and 6am with temporary traffic lights in place to manage traffic. The work will require some overnight closures which drivers will be advised about in advance.
Highways England Project Manager, Chris Corcoran, said:
By lining the whole section of the A66 we will be improving safety and making the road safer to travel along. The scheme will also provide drivers with smoother and safer journeys.
We will also be improving the busy junction at Melsonby crossroads and carrying out maintenance work which will also improve the road for motorists later in the scheme.
We are working to minimise disruption to motorists and we ask that they drive carefully and follow the clearly signed diversion routes for the duration of this work.
The final stage of the work is planned to be completed by December 2015.
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.