Johnson's finance and health secretaries quit on Tuesday, along with several in more junior roles, saying they could no longer stay in government after the latest in a series of scandals blighted his administration.
With mounting calls for Johnson to go, he showed his determination to stay in office by appointing businessman and education minister Nadhim Zahawi as his new finance minister, and filling some of the other vacancies.
Zahawi told reporters he would look at all options to rebuild and grow the struggling economy and tame surging inflation, when asked if he would cut taxes such as corporation tax.
The level of hostility Johnson faces within his party will be laid bare later on Wednesday when he appears in parliament for his weekly question session, and before the chairs of select committees for a scheduled two-hour grilling.
"I suspect we will have to drag him kicking and screaming from Downing Street," one Conservative lawmaker told Reuters, speaking on condition of anonymity. "But if we have to do it that way then we will."
Johnson, a former journalist and London mayor who became the face of Britain's departure from the European Union, won a landslide election victory in 2019 before taking a combative and often chaotic approach to governing.
His leadership has been mired in scandals and missteps over the last few months, with the prime minister fined by police for breaking COVID-19 lockdown laws and a damning report published about the behaviour of officials at his Downing Street office who breached their own lockdown rules.
There have also been policy U-turns, an ill-fated defence of a lawmaker who broke lobbying rules, and criticism that he has not done enough to tackle a cost-of-living crisis, with many Britons struggling to cope with rising fuel and food prices.
The Times of London newspaper said Johnson's "serial dishonesty" was "utterly corrosive" of effective government.
"Every day that he remains deepens the sense of chaos," it said. "For the good of the country, he should go."
The latest bout of drama at the heart of British power comes as the economy deteriorates rapidly, with some economists warning that the country could tip into recession.
The latest scandal saw Johnson apologising for appointing a lawmaker to a role involved in party welfare and discipline, even after being briefed that the politician had been the subject of complaints about sexual misconduct.
Downing Street's narrative changed several times over what the prime minister knew of the past behaviour of that politician, who was forced to resign, and when he knew it.
That prompted Rishi Sunak to quit as chancellor of the exchequer - the finance minister - and Sajid Javid to resign as health secretary, while ten others left their junior ministerial or envoy roles.
"It is clear to me that this situation will not change under your leadership - and you have therefore lost my confidence too," Javid said in his resignation letter.
Several of the ministers cited Johnson's lack of judgement, standards, and inability to tell the truth.
A snap YouGov poll found 69% of Britons thought Johnson should step down as prime minister but for the time being the remainder of his top ministerial team offered their backing.
"I fully support the prime minister," Scottish Secretary Alister Jack said. "I am sorry to see good colleagues resign, but we have a big job of work to do."
A month ago, Johnson survived a confidence vote of Conservative lawmakers, and party rules mean he cannot face another such challenge for a year.
However, some lawmakers are seeking to change those rules, while he is also under investigation by a parliamentary committee over whether he lied to parliament about COVID-19 lockdown breaches.
Nominations are expected to open on Wednesday for the executive of the so-called 1922 Committee that sets the rules for leadership confidence votes. Johnson critics hope to elect enough people to change the rules to allow another such vote before the 12-month grace period allows.
Were Johnson to go, the process to replace him could take a couple of months.
Only two-and-a-half years ago, the ebullient Johnson won a huge parliamentary majority on a promise to sort out Britain's exit from the European Union after years of bitter wrangling.
But since then, his initial handling of the pandemic was widely criticised and the government has lurched from one predicament to another.
Although Johnson won wider plaudits for his support of Ukraine, a lift in his personal poll ratings did not last. His Conservatives trail the opposition Labour Party and his own popularity ratings are at all-time lows.
Johnson's combative approach towards the European Union has also weighed on the pound, exacerbating inflation which is forecast to surpass 11%.
"After all the sleaze, the scandals and the failure, it's clear that this government is now collapsing," Labour leader Keir Starmer said.