Amber Rudd has quit the cabinet and surrendered the Conservative whip saying she cannot “stand by” while “moderate Conservatives are expelled”.
The work and pensions secretary said she no longer believed leaving the EU with a deal was the government’s “main objective”.
Ms Rudd described the sacking of 21 Tory MPs on Tuesday as an “assault on decency and democracy”.
No 10 said it was “disappointed” by the resignation of a “talented” minister.
But a spokesperson added that “all ministers who joined the Cabinet signed up to leaving the EU on 31 October come what may”.
A senior government source said “resignations to chase headlines won’t change the fact that people want Brexit done so that government can deliver on domestic priorities”.
Labour said Ms Rudd’s resignation showed the government was “falling apart”.
The MP for Hastings and Rye, who supported Remain in the 2016 referendum, said her resignation had been “a difficult decision”.
“I will be considering my position – whether I will stand as an independent Conservative should there be an election coming up,” she told the Sunday Times.
I have resigned from Cabinet and surrendered the Conservative Whip.
I cannot stand by as good, loyal moderate Conservatives are expelled.
I have spoken to the PM and my Association Chairman to explain.
I remain committed to the One Nation values that drew me into politics. pic.twitter.com/kYmZHbLMES
— Amber Rudd MP (@AmberRuddHR) September 7, 2019
In her resignation letter to PM Boris Johnson she said: “I joined your cabinet in good faith: accepting that ‘No Deal’ had to be on the table, because it was the means by which we would have the best chance of achieving a new deal to leave on 31 October.
“However I no longer believe leaving with a deal is the government’s main objective.”
Her resignation comes after a week of setbacks for the prime minister, when a cross-party group of MPs seized control of the Parliamentary agenda.