The A66 alongside Bassenthwaite Lake will be closed overnight from 8pm tomorrow until 6am on Sunday.
A diversion will run between High Hill junction and Crosthwaite roundabout.
Workers are on site to protect the road from flooding in a £1.5 million scheme.
They are raising parts of the carriageway and making sure the stability of the embankment at the western end of the dual carriageway is improved.
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