A mile-long stretch of the A66 between Kirkby Thore and Low Moor, east of Penrith, is to close for seven weekends.
The road will close at 10pm on Fridays and will re-open at 3am on Mondays.
Engineers say the roads old foundations need to be completely rebuilt.
Motorists will face diversions along the A69 to the north or the M62 to the south.
The closure will start on 7 September.