Operators London Northwestern Railway and Avanti West Coast say none of their trains will run between MK and London Euston on all four days of Easter.
And the lines will be shut down again for three days over the May Day weekend.
Shuttle trains will connect Northampton and Milton Keynes with some services replaced by buses to Stanmore, from where passengers can reach central London by underground.
Some services north of Northampton will also be disrupted by more engineering work between Coventry and Birmingham with buses running between Rugby and Birmingham International.
Despite the massive shutdowns across seven days in a spell of 18 days between April 15 and May 2, Network Rail insists the majority of the country's rail network will be "open as usual".
■ Click HERE for full details on London Northwestern Railway Easter services
■ Avanti West Coast is due to confirm trains times for Easter HERE in the next few days.
Passenger director for the North West and Central region, Dave Penney, said: “There is never an ideal time to shut the railway and we have to carefully balance the best time to do this essential work with the needs of our passengers.
"Long bank holiday weekends continue to give our engineers the time they need to close the railway for complex jobs like track replacements and bridge overhauls while disrupting the fewest number of people.
“I’d urge people to travel before and after these big jobs need to close sections of railway, so they have the smoothest journey possible. Please plan ahead and check National Rail Enquiries so you know exactly what to expect.”