Work on an £81 million improvement plan at Watford in Hertfordshire means that the West Coast line will be closed between London's Euston and Hemel Hempstead in Hertfordshire today and tomorrow.
The Watford work will affect services run by Virgin Trains, London Midland, London Overground and Southern, with some disruption continuing on Monday.
The same closure will be in place from Saturday, August 16 to Monday, August 18 and also from Saturday, August 23 to bank holiday Monday, August 25.
A NR spokesman said: "We're investing millions to build a better railway."
Work has been scheduled now to lessen any disruption, the spokesman added.