An overrunning engineering project shut the line between Reading and London Paddington at the end of last year.
Major work, including extensive signalling improvements, is being carried out on the route from Good Friday to Easter Monday.
Network Rail said it had "hundreds of buses" ready in case it overruns.
Julian Burnell, from Network Rail, said the disruption was needed to allow for the last major stage of work on the Reading station redevelopment to be completed.
He added: "This is a very big project, dealing with one of the biggest bottlenecks anywhere in the country.
"I can't say there's absolutely no danger [of an overrun at Easter], but we have done everything in our power to get it finished in good time. There are hundreds of buses waiting if that happens."
On 27 December, King's Cross station was shut and Paddington was closed for part of the day after engineering works took longer than expected.
A number of projects will take place over the Easter break, including a closure of the line between Hayes & Harlington in West London and Didcot Parkway in Oxfordshire while further work is carried out on the Crossrail project.
Network Rail has promised to do "everything in its power" to stop a repeat of the rail chaos at Christmas when it carries out work over Easter.