Over the next five years, work will be carried out on the M74 and A74(M), with improvements being made to the carriageway.
The motorway is used by more than 30,000 vehicles a day.
Plans for the upgrade include the resurfacing of stretches of road equivalent to the size of 2000 football pitches.
Work is due to begin at the end of this month and traffic management measures will be in place.
The section between junction 22 Gretna and junction 12 Millbank will be upgraded, with the work carried out by Autolink.
It has a contract with the Scottish Government's transport agency, Transport Scotland, for the road.
A spokesman for Transport Scotland and Autolink said: "This busy motorway carries more than 30,000 vehicles a day and is the main route between the Border and the Central Belt.
"This project is being delivered in several phases over the next five years and, on completion, will deliver over 80 miles of new road surface – equivalent to 200 football fields.
"We are working closely with local communities to ensure they are kept abreast of these works as they are delivered.
"Our aim is to minimise disruption but traffic management is essential for the safety of road workers and users alike."
Glasgow's extension of the M74, which cost £445million, to build opened last summer.
But as reported in the Evening Times, the road has been at the centre of a major probe after engineers discovered part of it was sinking.
The fault is located in the fast lane, shortly before the Polmadie slip road at Junction 1A.
Gallons of liquid cement grout could now be injected under the affected stretch.
matty.sutton@ heraldandtimes.co.uk
