Sadiq Khan criticised all sides and called on the unions to cancel the strikes lined up for next week, though he took particular aim at the government over its inaction.
"The unions should cancel the strikes and get back to the negotiating table, but the government are washing their hands of this crisis and abandoning commuters in this process," he said.
Services have been beset by delays and disruptions as a raft of strikes have been held throughout the year in a long-running dispute over the role of guards on trains.
“The chaos on the government-run Southern services this week is in stark contrast to Transport for London (TfL) – who successfully persuaded the unions to call off their planned strike on the underground through engagement and negotiation," he added.
The mayor also took the chance to plug his last-ditch bid for TfL to take over suburban rail services in the capital, saying the ongoing chaos showed why commuter rail lines, including Southern, Southeastern and South West, should be devolved to TfL.
He said: "It is absolutely clear that commuters would suffer from fewer strikes if TfL controlled these routes."
The mayor's plan was rejected by transport secretary Chris Grayling earlier this week, but he will make a final push in the next few weeks to get the government to change its mind.
For its part, the government has criticised the unions for "politically motivated" walkouts.
Grayling wrote to Brighton Kemptown MP Simon Kirby last month saying industrial action lined up was "politically motivated" and "designed to create maximum disruption".
He wrote: "We cannot allow the unions to dictate how or whether the railways should be modernised or not. They are seeking the right to determine when a train should be cancelled to inconvenience passengers, even in circumstances when this doesn't need to be the case."
And earlier this month, rail minister Paul Maynard MP reaffirmed the government will not be intervening, saying passengers wouldn't thank it for "costly intervention". Maynard said he understood people were impatient for action, "but when we take action it has to be the right action".
The government also recently unveiled a compensation package for long-suffering Southern season ticket holders, who will be able to claim a refund for the equivalent of one month's travel.
It comes after Southern owner Govia Thameslink Railway (GTR) failed in its legal challenge to hold off Aslef strikes next week. A High Court judge did though give GTR leave to appeal against the decision.