Services in London, Manchester, Bristol, Edinburgh and Glasgow are among those affected as 13,000 rail workers begin the £70m upgrade to tracks.
The engineering works will take place from Good Friday to Easter Monday, April 14-17, with many trains subjected to speed limits and diversions.
Network Rail said it is carrying out the work over Easter as fewer passengers use the railways during that period.
However, families wishing to get away as the school holidays begin will see their breaks get off to a chaotic start.
Services to London Heathrow and London Gatwick airports, will be affected, while the biggest disruptions will include the closure of the line between London Liverpool Street and Essex, hitting operators such as Great Anglia and TfL Rail.
Bus replacement services will be used on several services into Bristol Temple Meads, and on several lines in the West Midlands, affecting Birmingham New Street.
In Scotland, there will be no CrossCountry or Virgin Trains East Coast services between Edinburgh and Glasgow Central. ScotRail will also be running bus replacement services, with many trains diverted.
Network Rail’s managing director for England and Wales, Phil Hufton, insisted that most services will not be affected.
He said: “This Easter, thousands of rail workers will be working round the clock to deliver our Railway Upgrade Plan.
“This will provide faster, better services in the long run and help relieve overcrowding to respond to the huge growth on Britain’s railways.
“We know that many people want to use the railway during the Easter holidays and the good news is that over 95% of the network is unaffected by this work.
“But there will be some services that are impacted and so we strongly advise passengers to plan their journeys in advance.”
Top pic: Rex