Southern Railway has "strongly advised" passengers not to travel for most of the rest of the week after losing a court bid to halt strikes by drivers.
Hundreds of thousands of passengers will now have to work from home, take time off, or attempt to drive because of the huge disruption the walkout will cause.
Members of the drivers' union will strike tomorrow, Wednesday and Friday in a dispute over driver-only trains.
Southern's owners, Govia Thameslink Railway, lost a legal bid in the High Court last week to stop the strikes, and decided to lodge an appeal.
Three judges in the Court of Appeal backed High Court judge Sir Michael Burton's refusal to grant an injunction blocking what GTR called "unprecedented" strike action.
GTR argued the action would unlawfully restrict freedom of movement provisions under EU law.
But, Lord Justice Elias, Lord Justice Lewison and Lord Justice Lloyd Jones said they were not prepared to grant an injunction.
GTR chief executive Charles Horton confirmed there will be no services on strike days and "severe disruption" during an ongoing overtime ban.
He called for fresh talks at the conciliation service Acas.
Aslef general secretary Mick Whelan said drivers had been forced to strike because of the company's "intransigence".
Around 300,000 passengers travel on 2,242 Southern services every weekday, including busy commuter routes from Sussex to London Victoria.
They have suffered months of disruption because of the Aslef dispute and a separate row with the Rail, Maritime and Transport union over changes to the role of guards, as well as staff shortages, staff sickness and other problems such as signal failures.
The shutdown of Southern's services will be the worst disruption since the railways were hit by a lengthy strike by signal workers in the mid 1990s.
RMT drivers on Southern will also be on strike, while the guards will launch a fresh 48-hour walkout from next Monday, and a three-day stoppage from New Year's Eve.
Aslef is also planning a week-long strike from January 9.
Mr Horton said he was " disappointed" at the Appeal Court's decision, adding: " We had a responsibility to the travelling public to do what we could to stop this unprecedented strike action.
"Regrettably, there will be no train services for passengers tomorrow, Wednesday and Friday. We strongly advise people not to travel. In addition, there will be severe disruption every day during the ongoing industrial action because of the union's overtime ban.
"This is wholly unjustified and unnecessary industrial action. The widespread use of drivers operating trains is perfectly safe both in Southern and elsewhere in the UK where a third of trains operate this way every day.
"We will now be asking Acas to convene urgent and immediate talks between GTR and Aslef. Our aim is to find a resolution to their dispute so we can bring an end to the misery being suffered by the travelling public."
Mr Whelan said the union wanted Southern to negotiate "in good faith", adding: "We have tried everything possible this year to reach a sensible and workable compromise with Southern in the interests of passengers and management as well as of staff.
"We have always been prepared to sit down and talk, because we have always believed it is, or should be, possible to do a deal - as we did with ScotRail - but the company, encouraged by the Department for Transport, has not been prepared to negotiate with us."
Aslef denied company claims that it had refused to attend peace talks over the weekend.
Mr Whelan told BBC Radio 4's PM programme that the dispute was due to the "intransigence" of the train operator and Government.
Asked how he felt about reports people would miss cancer treatment appointments due to the strikes, the Aslef chief said: "I think that's rather poignant, I've got a few family issues at the moment. I would hate that to happen to anybody. But I would also hope that the appropriate medical and ambulance facilities, or other facilities, will be put in place to get those people to their appointments."
Pressed on the fact some patients from across the South East would be impacted, Mr Whelan said: " And that again would be more reason for people to be less intransigent and sit down and talk to us reasonably about what we can do to have a safer operating railway in the interest of everybody."
Mr Whelan said Southern Railway had contacted him to suggest going to Acas late Sunday, but Aslef said they would only do so if the company called off the court action.