Sajid Javid warned Tory cabinet ministers "not doing something is an active decision" as he pulled apart Boris Johnson's leadership in the Commons.
Refusing to "risk losing my integrity", Mr Javid said "enough is enough" adding, "there's only so many times you can turn that machine on and off before you realise something is fundamentally wrong".
The former Health Secretary wished his cabinet colleagues "well", adding "they have their own reasons", drawing laughter from many in the chamber.
But he said a "team is as good as its team captain and a captain is as good as his or her team".
Before Mr Javid made his statement Boris Johnson told MPs during PMQs his job is to "keep going" after a Tory backbencher asked what circumstances would push him to leave No10.
The PM's press secretary told reporters Mr Johnson is confident he still has the support of his backbench MPs and is certain he will be able to fill the posts of all ministers and parliamentary aides over the "coming days".
Mr Javid dramatically quit last night after Mr Johnson attempted to apologise for his handling of the Chris Pincher scandal.
"I also believe a team is as good as its team captain and a captain is as good as his or her team. So, loyalty must go both ways," Mr Javid said.
“The events of recent months have made it increasingly difficult to be in that team.
“It’s not fair on ministerial colleagues to go out every morning defending lines that don’t stand up and don’t hold up."
As Mr Javid spoke in the Commons, more Tory MPs continued to quit their Government positions and express their lack of confidence in the PM's leadership.
"I am deeply concerned about how the next generation will see the Conservative Party on our current course. Our reputation after 12 years in government depends on regaining the public’s trust.”
He said if the Conservative ideals of “decency” and personal responsibility and the rule of law could not be upheld, “the Conservative mission to extend freedom and prosperity and opportunity is all at risk”.
Mr Javid's statement comes less than 24 hours after he kicked off resignations last night when the PM admitted appointing Mr Pincher as Deputy Chief Whip in February was a "mistake".
In a letter posted on Twitter yesterday Mr Javid said: "Given the unprecedented scale of the challenges in health and social care, it has been my instinct to continue focusing on this important work.
"So it is with most enormous regret that I must tell you that I can no longer, in good conscience, continue serving in this government."
He said the public "rightly expect integrity" from the government, adding: "The tone you set as leader, and the values you represent, reflect on your colleagues, your party and ultimately the country."
Minutes later, Rishi Sunak broke cover and posted his own resignation letter.
The Chancellor said he had not taken the decision to step down lightly as Britain grapples with the cost of living crisis and the war in Ukraine.
But he added: "The public rightly expect government to be conducted properly, competently and seriously.
"I recognise this may be my last ministerial job, but I believe these standards are worth fighting for and that is why I am resigning."
