Engineering work will take place over nine weekends between late March and early June.
Engineers will be renewing or refurbishing track between Carstairs and the England/Scotland border from Sunday March 30.
Locations will include Abington, Thankerton and Symington while drainage improvements will be carried out at Elvanfoot and switches and crossings will be renewed at Kirtlebridge.
Further south, work to replace signals and lineside equipment north of Carlisle will be carried out. This includes replacing 16 points and installing 26 signals.
The work will take place on: March 30; April 6; April 13: April 19-21 (Easter weekend); April 27; May 3-4 (May Bank Holiday); May 10-11; May 31-June 1; June 8.
Buses will replace trains north of Carlisle to Glasgow (for Avanti West Coast services), Dumfries (for ScotRail services) and Edinburgh (for TransPennine Express services) on those dates, and between Preston and Carlisle on March 30.
Ross Moran, Network Rail Scotland Route Director, said: “Our engineers will be working hard to deliver these improvement projects as quickly as possible for our customers.
“The work we’re undertaking is vital to the long-term future of the line and will help to provide a more reliable railway for our passengers and freight customers.
“The complexity of the engineering work being completed means it can only be done by closing the line and we are urging passengers planning to travel on the West Coast Main Line over this period to check their journey in advance.”
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