An engineering train came off the track near Carnforth, Lancashire, and is affecting services by Northern Rail, TransPennine Express and Virgin Trains.
Some services have been cancelled and replacement bus services are being been laid on.
Journeys around the area are expected to be disrupted all day.
National Rail Enquiries website said:
Passengers are being warned to expect disruption until 21:00 BST on Sunday.
A derailed train has blocked lines on a major route between England and Scotland, National Rail Enquiries has said.