The biggest disruptions in the country will be on the West Coast Main Line into Euston, which is used by those in the West Midlands, North West and Scotland, due to the closure of the London station over the Easter weekend.
Network Rail has warned people to expect disruption and travel on alternative routes while the major works are being carried out on the current line and to prepare the station for HS2.
No trains will be running between Milton Keynes and London Euston, and people will need to switch to other lines or use the bus replacements.
Trains from Wolverhampton to London Euston will be starting and terminating at Milton Keynes Central where rail replacement bus services will be running to Bedford, where passengers can then board trains to London St Pancras.
Trains from Stafford will also start and terming at Milton Keynes Central, and have alternative routes with information available on the National Rail website or the train operator's website.
Affected train operators include Avanti West Coast, London Northwestern Railway and the London overground.
Football fans travelling from Liverpool and Manchester down to London for the FA Cup semi-finals will be affected too.
The West Midlands Metro is expected to remain suspended over the Easter holidays after cracks were found in the trams last month.
National Highways have said they will be lifting and completing hundreds of miles of roadworks in time for the Easter period, although the agency has not yet confirmed details.
However, drivers are being warned to expect long delays with the AA estimating that more than 27.6 million car journeys are planned between Good Friday and Easter Monday, with around half of those expected on Good Friday alone.
AA spokesman Tony Rich said: “The Easter holidays look set to give British tourism a much-needed boost as people cut back on overseas travel.
“With more than 27.6 million trips planned over the bank holiday weekend, we can expect significant congestion across the UK as people flock to coastal resorts and holiday homes.”
An AA survey of 14,000 drivers indicated that 53 per cent will use their car to go on holiday in the UK this year.
Latest Government figures show the average price of petrol at UK forecourts on Monday was 161.9p per litre, while diesel cost 176.0p per litre.
Those making Easter getaways by other modes of transport also face difficult journeys.
Several airlines and airports are struggling to cope with staff sickness and shortages, with a total of more than 100 daily flights being cancelled by easyJet and British Airways.
Passengers at Heathrow and Birmingham Airports have been reporting lengthy waits, while Manchester Airport has warned passengers to expect queues of up to 90 minutes due to staff shortages.
Charlie Cornish, chief executive of owner Manchester Airports Group, urged departing travellers to arrive three hours before their flight to avoid missing it.
Passengers have faced long delays and chaotic scenes in recent weeks, with queues trailing outside terminals to reach check-in desks and hordes of people waiting to get through security and to pick up luggage.
Mayor of Greater Manchester Andy Burnham said on Wednesday that problems causing long queues at Manchester Airport are likely to continue for two months.