The stretch of M1 between junctions 14 and 15 Northbound will be closed this weekend from 9pm on Friday 22nd October to 6am on Monday 25th October.
Currently, the stretch is being converted into a 'smart motorway' between Junction 13 and Junction 16 in Northamptonshire.
The huge amount of work still to do involves converting the motorway into four lanes of traffic with no hard shoulder.
In addition, there are new emergency areas, new roadside phones, safety barriers and CCTV to install.
But some of the northbound surface needs to be dug out so that tall vehicles and lorries can get under the Tongwell Lane Farm bridge.
A spokesman for National Highways, which is carrying out the £373million project, said: "Specialist teams will be working to lower the road surface underneath Tongwell Lane Farm bridge, near Newport Pagnell.
"The bridge is currently too low for larger vehicles once this section of the M1 becomes a four-lane motorway."
National Highways have issued the following advice for this weekend: "Drivers are encouraged to plan ahead, find alternative routes using the M40, A1 or M11 with the A14. We will also ask motorists to avoid this section of the M1 and surrounding roads if possible.
"Diversion routes will be clearly signed for the duration of this closure. We advise drivers to follow the signed diversion routes and not their own Satnavs.
""Please be considerate of residents living along the diversion routes when using these roads when the M1 is closed. We advise residents and business owners to allow extra time onto their journeys. We will do our utmost to complete the work as quickly as possible and keep noise and disruption to a minimum."
For any additional questions or concerns, please contact National Highways on 07469 391190.
If the work is completed sooner, National Highways have said the road will re-open ahead of plans.
Work on the section of road is currently set to be completed in 2022/23 - with an estimate cost of around £373m.