Mr Lewis told the Prime Minister in a resignation letter that he had “given you, and those around you, the benefit of the doubt”.
He continued: “I have gone out and defended this Government both publicly and privately,” the Northern Ireland Secretary told Boris Johnson in his resignation letter.
“We are, however, now past the point of no return.
"I cannot sacrifice my personal integrity to defend things as they stand now. It is clear that our Party, parliamentary colleagues, volunteers and the whole country, deserve better.”
Mr Johnson rejected calls to quit on Wednesday and dramatically sacked Cabinet rival Michael Gove, but was later hit with the departure of a third Cabinet minister – Welsh Secretary Simon Hart – and further demands to go from the Attorney General.
Mr Johnson met ministers in No 10 on Wednesday, where he was told he had lost the confidence of the Conservative Party and should not continue in office – but refused to listen.
Mr Gove was thought to have told the Prime Minister on Wednesday morning that it was time for him to quit.
That was followed by a delegation of Cabinet ministers going to No 10 to tell Mr Johnson he should stand down after losing the trust of his MPs.
Sir Graham Brady, chairman of the Tory 1922 Committee, spoke to Mr Johnson on Wednesday to set out the level of backbench opposition.
A new executive for the committee will be elected on Monday which could change the leadership rules, allowing for another confidence vote just a month after the last one – which Mr Johnson may lose given the way MPs have deserted him since Tuesday.
But a No 10 source said: “He has called Graham Brady’s bluff. All Graham could say is that there will be an election on Monday.
“A new 1922 committee on Tuesday could change the rules – but it’s not a given.
“The party could then demand a re-run of the no-confidence vote – but not a given.
“And the party could then decide to ditch the PM – but not a given.”
Brandon Lewis has resigned as Northern Ireland Secretary
Brian Lawless
Boris Johnson is facing calls to step down
House of Commons