Euston station has been closed for the first of three consecutive weekends as engineers rebuild a junction.
There will be no trains to or from the London station on 18-19 August, across the entire Bank Holiday weekend 25-27 August, and 1-2 September.
Network Rail is urging people not to travel at all on the West Coast Main Line during these times as the "vital" work is carried out at North Wembley.
About 150,000 people normally use Euston at the weekend.
Engineers are replacing track at a major intersection in Wembley - through which about 500 trains pass per day.
Euston station manager Joe Hendry said the selected dates were the best time of year to get the work done.
"For us, it's really important to get long periods of time to do these really complex and critical pieces of work," he said.
"It requires a full two days to be able to remove pieces of infrastructure and replace them."
The line affected serves Birmingham, Manchester, Liverpool and Glasgow.
Virgin Trains is lifting peak restrictions on trains to and from Euston each Friday before the planned closures to encourage people not to travel on the weekends.
London Northwestern Railway said it would provide buses to connect people with alternative routes to and from London, but admitted these journeys would be "significantly longer" than normal trips.
Euston station's shops and access to Tube platforms will remain available during the closures.
Network Rail urged passengers to check its website for the latest travel updates.