The A141 will be closed between Chatteris roundabout and Warboys roundabout in both directions for four days.
Cambridgeshire County Council (CCC) have the closure in place from February 22 to 25 from 8pm to 6am.
Drivers should expect delays, though access will be maintained.
A CCC spokesperson said: "Essential works are being carried out on maintenance of the highway. Drivers should plan alternative routes ahead of the closure."
The Peterborough and Cambridgeshire Combined Authority are working to deliver an improvement scheme north of Huntingdon to improve the congestion and delays on the A141.
The A141 is the main road from the fens and it is crucial for the whole Huntingdon and St Ives area: north-east, it connects villages and towns within rural Fenland; west, it links the wider region via the A14 and the A1.
The A141 is well-known for traffic jams that affect all road users, whether cycling, walking, travelling on buses and coaches, or riding horses.
Comments: Our rules
We want our comments to be a lively and valuable part of our community - a place where readers can debate and engage with the most important local issues. The ability to comment on our stories is a privilege, not a right, however, and that privilege may be withdrawn if it is abused or misused.
Please report any comments that break our rules.
Read the rules here