The motorway will be shut at Junction 10 between Wolverhampton and Walsall from Friday night as a new bridge is installed as part of a £78 million revamp.
The route is being shut off in both directions to allow for 44m-long steel beams, which form part of the new bridge, to be lifted into place.
It marks the third time lucky for the work on the congestion-busting revamp of the roundabout after it was delayed twice by Highways England.
Road chiefs say the work is a "significant step" in the scheme which will see the 50-year-old bridges currently in place across the motorway replaced.
The number of lanes around the bottleneck junction will also be increased from two to four – helping to cut congestion and allow traffic to run smoothly.
The junction will close on Friday at 8pm and will reopen at 6am on Monday and an ‘up and over diversion’ will be in place – meaning traffic will leave the M6 at Junction 10, funnelled over the roundabout to head back onto the motorway on the other side of the closure.
While vehicles will still be able to get from one side of Junction 10 to the other, heavy congestion is expected as vehicles make their way across the bridge, which has traffic lights and is busy at the best of times.
As a result, motorists have been urged to avoid the area. To avoid the closure, drivers can get off the M6 at nearby Junction 9 for Wednesbury or Junction 11 if heading southbound.
From Junction 11, drivers can use the A462, the B4210 and the A35 Green Lane to reach Walsall, before using the ring road and following signs for the M6 to rejoin at Junction 9. Northbound drivers can use the same route in reverse to rejoin at Junction 11.
The junction serves thousands of drivers every day. Traffic regularly backs up on the Black Country Route and Wolverhampton Road at peak times and transport chiefs say the major project will help solve some of the issues faced by drivers. Work began at the junction at the start of the year.
Highways England’s project manager, Annie Hyett, said: "The beam lift is a huge milestone in the construction of the new bridges but we appreciate that any road closures can be frustrating for people.
"We need to fully close the M6 because we’re using specialist machinery and it’s vital that we keep those doing the work and motorists safe.
"Once complete, the improvements to this junction will tackle the severe congestion that drivers, businesses and the local communities have been encountering for a long time.
"This is a busy junction and we would urge anyone travelling along the M6 over the weekend of August 6 to 9 to look at alternative routes if possible and to allow extra time for journeys if not.
"We are grateful to people for their patience while we carry out this significant construction work that will bring smoother, more reliable and safer journeys for road users.”
A team of around 50 workers will be involved as the beams, each weighing 130 tonnes, are delivered as an abnormal load to the site and lifted into place on the north bridge over the weekend.
Both carriageways of the motorway will be closed while the work takes place at the junction to ensure the safety of workers and road users. Highways England and Walsall Council, supported by the Black Country Local Enterprise Partnership, have joined forces to fund the upgrade. Contractor John Sisk & Son is carrying out the work.
The beams for the south bridge will be lifted into place later in the year and will also require the M6 to be closed. The old bridges will be demolished later.
As well as work on the junction itself, the westbound carriageway of the busy Black Country Route is being widened from two to three lanes from Junction 10 to Marshlands Way.
The congestion at Junction 10 was identified as one of the main transport issues facing the region in the West Midlands Strategic Transport Plan.