The second resignation came just 30 minutes before the prime minister had to face the Commons, amid the mounting anger of Leave-backing Tory MPs that the deal struck on Friday is a sell-out.
It is thought that Mr Johnson was furious with briefings that he had signed up to the agreement at Chequers – despite also calling it “a turd”.
Tom Watson, Labours deputy leader, said: “Theresa May’s government is in meltdown. This is complete and utter chaos.
“The country is at a standstill with a divided and shambolic government. The prime minister can’t deliver Brexit and has zero authority left.”
Donald Tusk, the European Council president, immediately suggested the twin blow might yet force the UK to rethink leaving the EU altogether.
“Politicians come and go but the problems they have created for people remain,” he tweeted. I can only regret that the idea of #Brexit has not left with Davis and Johnson. But…who knows?”
There was also an instant response from Ruth Davidson, the Tory leader in Scotland who has clashed repeatedly with Mr Johnson. She tweeted: “The prime minister is correct to accept the Foreign Secretary’s resignation.”
The bookies Ladbrokes immediately rated the prime minister odds-on to be forced out of Downing Street this year – with Michael Gove, the environment secretary, favourite to replace her.
In a terse statement, a Downing Street spokesman said: “This afternoon, the prime minister accepted the resignation of Boris Johnson as Foreign Secretary.
“His replacement will be announced shortly. The prime minister thanks Boris for his work.”
Speculation grew that Mr Johnson was about to quit when he failed to attend a meeting of the government’s Cobra emergencies committee, following the fatal Salisbury poisoning.
He also missed a summit of Western Balkan nations being held in London – despite the UK hosting the event as part of attempts to show it would remain a major European player.
Michael Roth, the German Europe minister, tweeted his displeasure, saying: “We’re still waiting for our host….”
In the Commons, there was laughter when the prime minister paid tribute to her “right honourable friends” who had resigned – and shouts of “who’s next?”
Mr Davis was praised for his “hard work’ through two years of negotiations – and Mr Johnson for his “passion” in championing a “global Britain”.
Earlier, the former Brexit Secretary accused Ms May of “giving away too much, too easily” in the Brexit talks, but denied his dramatic resignation was intended to topple her.
The prime minister was misleading the country by claiming her proposals would allow the UK to take back control, because a “common rule book” with the EU on goods would make it a rule taker.