Major delays are expected on the M6 motorway connecting Birmingham and the North West for 10 weeks.
A contraflow will cause narrow lanes from junctions 14 to 15 through Staffordshire from 3 March.
A 40mph limit will apply through the work on one of the country's busiest stretches of road. The Highways Agency said the work was unavoidable.
Drivers in Stoke-on-Trent and Stafford are expected to face delays as some motorists switch to the A34.
'Avoid peak times'
The work is to be carried out on the M6 between the Eccleshall Road and A51 Sandyford bridges.
It will involve repairing the road surface, upgrading central reservation safety barriers and drains, new road markings and bridge repairs.
Hauliers will face extra delays, with vehicles wider than 9ft 6ins having to be escorted through the three-mile stretch.
A Staffordshire County Council spokeswoman said: "We will be advising people to avoid travelling at peak times and stagger their routes wherever possible.
"They should also look into the possibility of car sharing and using alternative routes."