She also faces a motion by opposition parties and her own nominal allies in the Northern Irish DUP for her government to be found in contempt of parliament for failing to publish in full the legal advice on Brexit that it commissioned.
The defeat means the government will now have to publish the legal advice given to Cabinet ministers on the Brexit deal - despite insisting it would not be in the national interest to do so.
It is still not clear what would happen if the proposed agreement is voted down by Parliament, but an amendment put forward by former Attorney General Dominic Grieve suggests the possibility of "no deal" is now less likely.
The amendment gives MPs the power to instruct the government what action to take if May's Brexit deal is, as expected, voted down in Parliament.
A judge in the European Union ruled on Tuesday before this vote took place that the United Kingdom could cancel its Brexit plans without getting the approval of all the remaining EU member states.
He added: "Even at this eleventh hour, I would urge ministers to step back from the brink and to not go down in history as the first Government to be found in contempt".
Few in the House of Commons, the lower house, seemed to have been won over on Monday.
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The Prime Minister caved in moments after MPs decided her ministers were in "contempt" of Parliament.
An attempt by ministers to refer the whole issue to a committee of MPs was earlier defeated earlier by four votes.
"We have listened carefully and in light of the expressed will of the House, we will publish the final and full advice provided by the attorney general to cabinet", Leadsom told parliament. Pro-EU lawmakers and the DUP, which props up her government, say they will vote against, and the main opposition Labour Party says it will try to unseat her.
At the Commons Business Committee, Toyota Europe deputy managing director Tony Walker warned that without a deal to protect cross-continent supply chains, its operations in the United Kingdom would face major challenges.
"If I had banged the table, walked out of the room and at the end of the process delivered the very same deal that is before us today some might say I'd done a better job". They claim that London will be forced to follow European Union rules without having a say in them; they also say that the European Union common external tariff will prevent London from enforcing free trade agreements on goods with non-EU countries.
"I never said this deal was ideal, it was never going to be".
Mrs May said Britain will leave regardless of any future decision by the EU's top court and that the choice is between her deal or no deal.
The ECJ's advocate general Manuel Campos Sanchez-Bordona said the United Kingdom could withdraw its notification to leave the European Union before its exit in March 2019 without needing the approval of the other 27 states.
If she loses, May could call for a second vote.