Engineering works between Bedford and Harpenden will force passengers onto the roads, more than doubling journey times to and from the capital on Saturday (May 7) and Sunday.
It is the second of several weekends throughout 2022 where parts of the railway are shut down.
East Midlands Railway trains will start and finish at Bedford with passengers being offered a 55-minute bus journey to Hitchin to connect with services to King's Cross.
Thameslink services which nomally terminate at Bedford will run to Harpenden with bus connections to Luton and Luton Airport Parkway.
The disruption will affect Luton Town fans heading to Kenilworth Road for the club's last game of the season against Reading on Saturday.
Passengers are advised to check the National Rail Enquiries website for exact timings before setting out on weekend journeys.
Operators promise the upgrade work being carried out will make sure "better journeys are on track" for Northamptonshire passengers.
Network Rail says around 740m of track will be renewed between Luton and Bedford as engineers continue to upgrade the railway, allowing more trains to run at higher speeds under the overhead power lines.
EMR’s customer services director, Neil Grabham, said: “We’re encouraging any passengers travelling to or from London this weekend to allow extra time for their journey, as there is a rail replacement service between Bedford and Hitchin.
“We would like to thank our passengers for their patience whilst the track Luton and Bedford is upgraded.”