Thousands of Liverpool supporters are expected to make the journey to the capital to watch their team take on Cardiff City in the cup clash on Sunday afternoon.
But those planning to travel on the rail network have been advised to alter their plans.
Virgin Trains said an engineering train derailed at Winsford, in Cheshire, overnight, leaving the line between Liverpool and Crewe and Warrington and Crewe blocked.
Issuing an apology, the operator recommended those travelling to London consider driving to Crewe, Stafford or Stoke stations and taking the train from there.
A Virgin spokesman said: "Due to the derailment of an engineering train at Winsford overnight, the line between Liverpool and Crewe and Warrington and Crewe is blocked.
"Due to the high number of passengers intending to travel from Liverpool/Runcorn to London for the football at Wembley it is recommended that if possible they consider driving to Crewe, Stafford or Stoke stations and use the rail services from there.
"Coaches will also be provided to connect Liverpool and Crewe and Runcorn and Stafford.
"Virgin Trains apologises for the disruption and is doing everything it can to minimise the major disruption caused by the derailment."
National Rail said there would be no trains from Liverpool Lime Street to Crewe until further notice.
London Midland trains are also affected by the derailment.
Steven Knight from Virgin Trains said: "Today is an extremely busy day for us out of Liverpool and we have an army of people out this morning doing everything they possibly can.
"We are at the moment attempting to get coaches to Liverpool and Runcorn so they can provide a shuttle service to Crewe and connect with our train services to London.
"My advice to anyone intending to drive into Liverpool or Runcorn to get the train, if they are able to drive to Crewe, Stoke-on-Trent of Stafford stations then they can use the train services from there."
The Preston to Crewe route is also affected.
Fans looking forward to the big day have begun spreading the news of the delays on social networking sites.
Citta Nirmala wrote on Twitter: "Oh God: ( All trains from Liverpool to London cancelled due to train crash, nightmare day for reds travelling from Liverpool".)
While AlastairGW tweeted: "All trains between Liverpool and London are cancelled? What have he Cardiff fans been up to?"
Passengers travelling between Liverpool Lime Street and Crewe towards London Euston have been advised to travel via Chester or Manchester Piccadilly, while those heading to the capital from Runcorn have been told to take a replacement bus service to Crewe.
Commuters travelling from Wigan North Western or Warrington Bank Quay have also been advised to travel to London via Manchester Piccadilly.
Further details of the problems and the impact on Sundayy's services can be found at www.nationalrail.co.uk/service-disruptions/today.html.
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