At the same time as ministers and Number 10 staffers were deserting her, Theresa May had endure a painful Commons debate in which both sides pronounced that her deal was dead.
Dominic Raab quit the role on Thursday over "fatal flaws" in the agreement.
The prime minister will answer callers' questions about the plan on LBC radio on Friday morning.
First Dominic Raab resigned from the cabinet, with fellow hard Brexiter Esther McVey following in his footsteps soon afterwards.
Mrs May today said she faces a personal risk from medicine supplies being unable to get through Britain's ports.
Rumours are circulating that Environment Secretary Michael Gove is considering whether or not to follow him out of Government.
"Given the past performance of the EU, there is every possibility that the UK-EU trade deal that we seek will take years to conclude", he wrote.
"Leadership is about taking the right decisions, not the easy ones".
Brexit minister Suella Braverman and Northern Ireland minister Shailesh Vara also quit.
Looking exhausted and drawn, she said she believed in her Brexit plan "with every fibre of my being", and ruled out a People's Vote.
Saying her deal is "in national interest" and calls on country to "unite behind" the deal.
Other ministers, including Esther McVey, who reportedly argued heatedly with the Chief Whip at the Cabinet meeting, and Penny Mordaunt, a hardened Brexiteer, are being closely watched this morning to see their next move.
The government, for today at least, is at the mercy of events not in control.
With her party in revolt, her colleagues departing - some determined to usher her out of office - we can't, and don't know yet, if Brexit can happen as planned, perhaps, if at all.
Tory MP Mark Francois said, with Labour, the SNP, the Lib Dems and the DUP planning to vote against it - alongside, he said, more than 80 Tory MPs, it was "mathematically impossible to get this deal through the House of Commons" and it was "dead on arrival".
"You're absolutely right, for a lot of people that voted leave, what they wanted to do is make sure that decisions, such as people that come into this country, are taken by us here in the United Kingdom and not by Brussels".
But he echoed the prime minister in calling the agreement a "decisive" step and suggested he could now call a summit of European Union leaders to consider approving it.