Trains to London Victoria, Charing Cross and Cannon Street are affected.
Passengers were urged to check the Southeastern trains website before they travel, with more than 50 services currently delayed or cancelled.
Southeastern apologised, saying it had been caused by "a complete loss of signalling".
The signal is now working again, but delays are expected to continue.
Train passengers are being advised they can use their tickets on London Underground, Docklands Light Railway and London Overground, and on London Buses between Lewisham and central London.
Commuters delayed by more than half an hour can claim compensation.
The general secretary of the RMT union blamed the problem on a "toxic mix of massive overcrowding and infrastructure failures".
A Network Rail spokesperson said: "We apologise for the delays passengers experienced this morning on the line through London Bridge to Charing Cross and Cannon Street.
"The signalling problems have been fixed but there are delays as the service recovers. We would advise passengers to check the latest travel information on National Rail Enquiries or with their train operator."
A major signal failure at London Bridge has caused severe disruption for commuters trying to reach central London from Kent and the South East.