Rail journeys will be disrupted during both May bank holiday weekends as more than 900 engineering projects are carried out.
Several sections of the West Coast Main Line will be closed from May 4-6, including at London Euston and near Crewe and Glasgow.
Network Rail, the government-owned company responsible for Britain's rail infrastructure, warned that this will have a "major impact" on journeys, with Virgin Trains and London Northwestern Railway among the operators affected.
Alternative routes will be busier than normal and travel times will be extended.
The closure comes just two weeks after London Euston was shut over Easter.
There will be more changes to services on the West Coast Main Line as further work is carried out during the second bank holiday weekend next month, which runs from May 25-27.