Drivers face chaos as the road is closed to allow engineers to demolish a bridge in Bothwell, Lanarkshire, as part of a massive £500M works programme.
The M8 M73 M74 Motorway Improvements Project will see the busy route closed from 8pm on Friday to 6am on Monday.
The shutdown will stop access from the M73 to the M74 southbound at Junction 4 Maryville or to the M74 northbound at Junction 5, Raith.
Diversions will be in place but roads bosses have urged drivers to avoid the area.
Several Lanarkshire towns are due to launch their Christmas light displays this weekend including Lanark, Hamilton, East Kilbride and Rutherglen.
And football fans have been warned to plan ahead if they hope to travel to games at Motherwell’s Fir Park and Airdrie’s Excelsior Stadiums.
Rangers fans have also been warning fellow supporters ahead of Saturday’s home match against Dundee at Ibrox.
Motherwell FC said on their website: “Fans travelling to Fir Park on Saturday are advised to plan their journey due to part of the M74 being closed.”
While Airdrie told supporters: “Fans travelling to Saturday’s home match against Alloa Athletic are reminded that the M74 will be closed between Junction 4 Maryville and Junction 5 Raith over the weekend.
“Please plan an alternative route and allow extra time for your journey.”
Graeme Reid, Transport Scotland Project Manager for the M8 M73 M74 Motorway Improvements Project, said: “This is the most significant road closure we have implemented as part of the works and we are anticipating major delays on all approaches, the surrounding roads and the main diversion route.
“We are advising road users to plan their journey, avoid the area and surrounding local roads, and if possible, to use alternative modes of transport for the weekend.”
Signed diversion routes will be in place via the A725, A8 and the M73, although Transport Scotland is warning road users to expect major delays on all surrounding routes as a result of the M74 closure.
Motorists will continue to have access to the M74 southbound at Junction 5 Raith, and the M74 northbound at Junctions 4 Maryville and 3A Daldowie, however, there will be no access to Bothwell Services from the M74 southbound.
The next available service area is the M74 southbound at Junction 11, Happendon and Junction 13, Abington.
South Lanarkshire Council will be enforcing parking restrictions on a section of Bothwell Main St for the weekend and traffic signals will be monitored at key junctions.
Scotrail is providing extra capacity on the trains for the weekend.