Less than 24 hours before the vote, May flew to Strasbourg, France, to meet with European Commission President Jean-Claude Juncker to hammer out enough changes to the deal to secure its approval from Parliament.
There is concern the chaos would spread to markets and supply chains, and others fear it could cause shortages of food and medicines.
Both lawmakers and the public remain split between backers of a clean break from the European Union and those who favor continuing a close relationship, either through a post-Brexit trade deal or by reversing the June 2016 decision to leave.
"Therefore, the House has to understand and accept that, if it is not willing to support a deal in the coming days, and as it is not willing to support leaving without a deal on 29 March, then it is suggesting that there will need to be a much longer extension to Article 50. A solution must come from London", Dutch Prime Minister Rutte said on Twitter.
"The party is going to be fundamentally divided over this". The deal we've negotiated is the best and only one available.
Meanwhile, the Commons Brexit Committee called on Wednesday for Article 50 to be extended, with "indicative votes" for MPs to signal their preferred way forward.
Northern Ireland's 11 sitting MPs, including all 10 DUP MPs and Independent MP Lady Hermon, voted against the amended motion.
Even if the Malthouse plan were approved by the House Commons, the European Union would be unlikely to agree a transition period without a comprehensive withdrawal agreement in place.
Environment Secretary Michael Gove, standing in for May after she lost her voice in earlier debates, told parliament that tens of thousands of businesses were not prepared for a no-deal exit.
She was scathing of the Labour leader Jeremy Corbyn.
Dame Caroline attempted to withdraw the amendment, but it was moved by fellow signatory Yvette Cooper and won the support of a majority of MPs during a string of crunch Brexit votes on Wednesday evening.
That defeat is what has led to such unpredictable times.
However, she also said that "the options before us are the same as they always have been", reiterating that voting for a deal is the only way of avoiding no deal. That is the question that needs to be posed to which we expect an answer. Does it want to hold a second referendum?
"If it is one that takes no deal off the table forever that's a nonsense idea, because if you're going in to buy a auto, or buy anything, you would never say to the person on the other side: "Whatever terms you offer me, I will take it and I will walk out'".
"I think what we all want really is a genuine free trade agreement, not membership of a political club, and that is what that document did".
"I think it is still alive, I do", Ms Truss told BBC Radio 4's PM. But the mood has been hardening among European politicians, who seem reluctant to reopen negotiations for a withdrawal deal or grant a delay to Brexit without any specific goal.
In remarks released late Tuesday, Maas said the U.K. Parliament's decision to reject the deal "brings a no-deal scenario ever closer". If it passes, the United Kingdom would crash out of the European Union on March 29th with no arrangement with the bloc which would also mean a hard border between Northern Ireland and Ireland, a scenario that a majority of the MPs oppose.