The Prime Minister suffered another body blow to his authority as the Liberal Democrats overturned a massive Conservative majority to take the seat by almost 6,000 votes.
The result sent shock waves through Westminster after weeks of damaging headlines about Tory “sleaze” and reports of partying in No 10 in breach of Covid restrictions last year.
Speaking during a visit to a vaccination centre in Hillingdon, the Prime Minister said: "Clearly the vote in North Shropshire is a very disappointing result.
"I totally understand people's frustrations. I hear what the voters are saying in North Shropshire. In all humility I have got to accept that verdict.
"I understand that what voters want us, as the Government, to be doing at all times is to focus on them and their priorities."
Answering questions from reporters, Mr Johnson added: "I'm responsible for everything that the Government does and of course I take personal responsibility."
Asked which things going wrong under his watch were to blame for the defeat, he said: "I think that people are frustrated and I understand that...
"Basically what's been going wrong... is that in the last few weeks some things have been going very well, but what the people have been hearing... is just a constant litany of stuff about politics and politicians and stuff that isn't about them and isn't about the things that we can do to make life better.
"And so to that extent, of course, you're right - and I think the job of the Government is to make people like you... interested in the booster rollout and in skills and in housing, and in everything else that we're doing.
"And unfortunately, you're totally right, we haven't been able to get the focus on those issues."
The Prime Minister added: "I think my job is to get over what we're doing more effectively and to show people that, as a result of the fastest vaccine rollout and the fastest booster rollout in Europe, that we've got more jobs than before the pandemic began...
"I've got to put my hands up and say 'Have I failed to get that message across in the last few weeks? Has it been obscured by all this other stuff?' Yes, I'm afraid it has."
Mr Johnson has said he needs to "fix" issues like the reported Number 10 parties and the funding of the refurbishment of the No 10 flat.
"Those questions are exactly the kind of questions about politics and politicians and all those kind of things, the running of government, that I'm going to have to fix of course," he said.
"But the real issue people want to focus on is what we're doing to sort out the NHS, the investment we are putting in to get us through a very tough time and what we are doing to tackle the pandemic."
With the unexpectedly heavy defeat prompting renewed talk of a possible leadership challenge, senior Conservatives appealed for “calm” while warning that Mr Johnson had only a limited time to turn things around.
Sir Charles Walker, the vice chairman of the 1922 Committee of Tory backbenchers, said a leadership contest would be “completely self-indulgent” but added Mr Johnson had 12 months at most to make a difference.
)“The Prime Minister has got weeks, months, a year to sort himself out,” he told Times Radio.
“If we go on making unforced errors over the next three to six months or nine months, it will become a lot more serious. It’s serious now but it’s not at a critical level yet.”
Sir Geoffrey Clifton-Brown, the treasurer of the 1922 Committee said it was not the time for a “big blame game” but that Mr Johnson needed to stop the “self-inflicted own goals”.
“I want him to succeed, I am giving him the benefit of the doubt,” he told Sky News.
“But in doing that, as one of his seasoned backbenchers, I am asking him to think carefully how he governs the country and avoid these self-inflicted measures.”