Business minister Richard Harrington resigns to vote to give MPs more of a say.
Mr Harrington quit his post so he could vote for Oliver Letwin's amendment which would give MPs the chance to vote on a number of different Brexit options.
It comes after weeks of threatening to go as he implored the Prime Minister to take no deal off the table.
In his letter to Theresa May, he said the "government's approach to Brexit is playing roulette with the lives and livelihoods of the vast majority of people".
He was one of three ministers who threatened to back a Commons move to force a delay if Theresa May's deal was voted down last month.
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In the end he abstained rather than vote against the government.
Mr Harrington's letter continued: "I fear that no deal would be part of a giant economic experiment that is championed by a small minority of the economics profession, a small minority of the Conservative Party, and a small minority of the country.
"I have therefore decided that I resign from the Government to do all I can to prevent this from happening and will work with other concerned colleagues in these efforts. I hope you will now act in the national interest and enable Parliament this week to find a consensus which we can use as our negotiating position moving forward. I believe this is the only way to ensure true democracy.
"The Conservative Party has a deep and honourable tradition of putting the national interest before itself. It has also had a long history of being the party for business, entrepreneurs and supporting people to prosper and succeed.
"This is the moment to ensure this Conservative Government continues this proud tradition and necessary endeavour.
"It has been an honour serving this Government, and I will be proud and vocal in my support to you and your Government on all matters aside from Brexit."
