Engineers will work around-the-clock for 16 weeks to electrify the railway between East Kilbride and Glasgow from January 2025.
The project, part of a Scottish Government investment and delivered by Network Rail, aims to decarbonise rail services and enhance reliability for passengers.
Once completed in December 2025, the project will bring about several significant changes.
The railway from Glasgow to East Kilbride will be electrified, and new stations will be established at East Kilbride and Hairmyres.
The Hairmyres station will feature two platforms and an accessible footbridge.
A new footbridge will also be constructed at Busby station, while access at Giffnock will be improved with a new footbridge.
Clarkston will have a new station entrance.
To facilitate these improvements, from January 25 until May 18, no trains will operate on the line between East Kilbride and Thornliebank stations.
During this period, 22km of overhead power cables will be installed, and the double-track between East Kilbride and Hairmyres will be extended.
Near Busby, Clarkston, and Giffnock stations, the existing track will be lowered to accommodate overhead line equipment under some bridges.
Gerry McQuade, capital delivery director at Network Rail, said: "This programme of extended engineering works is a critical point in the delivery of the electrification of the East Kilbride line.
"We do appreciate the impact this will have both on those living closest to the line and to our passengers."
Mark Ilderton, service delivery director at ScotRail, said: "Unfortunately, during the 16-week closure, we will be unable to operate trains to and from East Kilbride, and an alternate transport plan will help to make sure customers are still able to travel.
“In the coming weeks, we will communicate the plan through all our customer information channels, including where replacement buses will operate, and the other routes available for customers.”
Passengers are advised to check the ScotRail or National Rail websites for information on the replacement bus service and to plan their journeys accordingly.
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