Hundreds of trains have been cancelled in a row over plans for drivers, instead of conductors, to operate carriage doors on the trains.
"The Prime Minister strongly condemns the strike action It's only going to cause more disruption and misery for passengers. We are deeply disappointed that union bosses are overlooking the impact that they are having on the public, and we obviously want to see the situation resolved," a Downing Street spokesperson said.
"This action has been forced on us by the arrogance and inaction of Govia Thameslink [parent firm for Southern railway] and the government who have made it clear that they have no interest in resolving this dispute or in tackling the daily chaos on Southern," RMT general secretary Mick Cash said.
"Our fight is with the company and the government who have dragged this franchise into total meltdown. We share the anger and frustration of passengers and we cannot sit back while jobs and safety are compromised on these dangerously overcrowded trains," he said.
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Southern is the main operator for Sussex and east Surrey regions of England, with services running to London, Kent, Hampshire and Buckinghamshire.
Last month, it brought in a reduced timetable in response to continued cancellations and delays, blaming issues with crew availability.
The Campaign for Better Transport and a Southern passenger group, the Association of British Commuters, plan to march from London Victoria station to the Department for Transport on Wednesday afternoon to hand in a "six-foot letter".
Britain's railway network is run by a series of firms like Southern since it was privatised in the 1990s.