Lines to London Euston will be closed throughout the three-day holiday weekend as Network Rail picks up work between Watford and Wembley started at Easter.
Trains will start and finish at Milton Keynes on Saturday, Sunday and Monday with buses connecting passengers to the capital.
East Midlands Railway and Thameslink services from Wellingborough and Bedford will run largely as normal but operators say they are likely to be busier than usual.
Network Rail bosses say the work is being done now to avoid clashes with the Queen’s Platinum Jubilee in June and this summer's Commonwealth Games in Birmingham.
Operators London Northwestern Railway and Avanti West Coast are telling passengers to “travel either side” of the bank holiday.
Network Rail’s West Coast South route director, James Dean, insisted the railway renewals will increase capacity through a key junction, meaning fewer delays and faster journeys for passengers and freight.
He added: “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 give our engineers the time they need to close the railway for complex jobs while disrupting the fewest passengers.
“Our advice is to travel either side of the bank holiday weekend and to plan ahead by checking National Rail Enquiries to see how your journey could be impacted by our essential upgrades to improve the railway for the future.”