Cumbria County Council is resurfacing a six-mile stretch of the A7 between Longtown and the M6 from Monday.
The closure will operate between 7pm and 6am to limit disruption. But it means people are likely to face delays or detours as work continues.
The improvements come as lobbying intensifies to improve the route north of the border.
The A7 action group has met Humza Yousaf, Scotland’s transport minister, who has promised to work with campaigners.
Dumfriesshire MSP Oliver Mundell said: “The A7 remains a hugely important connecting route to Carlisle for the people of Eskdale.
“These weeks of works will be a major inconvenience but this is a significant investment.”
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