On a testing night for Boris Johnson the Conservatives saw a 24,000 majority turned over by the Lib Dems in Tiverton and Honiton and also lost Wakefield to Labour.
It comes after the PM survived a confidence vote in his leadership in which more than two-fifths of his MPs voted to boot him out of Number 10.
However, Conservative MPs in the Black Country and Staffordshire have remained loyal to the PM, saying he still has their backing despite the "disappointing" results.
They conceded the party "has a lot of work to do" to restore confidence and called on the Government to "double down" on delivering on "issues that really matter".
Wolverhampton South West MP Stuart Anderson said: "They are not good results for us and it is never good to lose like that.
"Now we need to move forward and focus on what is important to the country. Boris won the confidence vote, so spending the next few months talking about ourselves will do nothing for the British people.
"There is no time for navel gazing. We need to continue delivering, and I believe Boris is the best man for Wolverhampton and the rest of the country."
Dudley North MP Marco Longhi told the Star he has "full confidence" in the PM.
"This is undoubtedly a big disappointment," he said of the by-election results. "People always expect results, and we have been slow, but also hampered by lockdowns that weren’t in anybody’s manifesto.
"We need to double down on delivering for people and show results on the top priorities people voted for.
"As far as the by-election results go, we’ve been here before several times when government parties lose heavily in by-elections and then win back at a general election. Delivery is key now."
Stourbridge MP Suzanne Webb said the results were "disappointing".
"The Prime Minister now needs to get on with the mission he has set out to level up, improve our infrastructure, our energy security, healthcare and productivity and drive ground-breaking legislation, like the Online Safety Bill, through Parliament," she said.
"My job to represent Stourbridge continues. I am working with the council on our shared £20 million Levelling Up Fund vision for Lye and my focus remains firmly on obtaining jobs and investment to improve the lives of local people."
Dudley South MP Mike Wood said the results were "obviously poor".
He added: "While it's not unusual for for governments to have bad by-election results in the middle of a Parliament, we certainly don’t want to have too many like that.
"We’ve clearly got a lot of work to do to restore confidence that we are going to deliver on the reasons why so many people in the Black Country voted for a Conservative government two-and-a-half years ago, and to show that we are the best option now to meet the massive challenges of helping families to deal with the high global costs of food and energy, rebuilding after the pandemic and resisting Russian aggression in Ukraine."
Lichfield MP Michael Fabricant said: "The mood in the tea room and elsewhere was that we would be lucky to hold Tiverton and Honiton. Although the result is disappointing it is no big surprise given that it is mid-term and in the middle of an industrial dispute.
"Frankly I'd be a lot more worried if I was Keir Starmer. Sure, he regained Wakefield – which had been Labour since 1932 – but it was hardly a major swing and certainly not enough to win a general election."
Mr Johnson, who is in Rwanda, has vowed to "keep going" in the wake of the results, which sparked the resignation of Tory chair Oliver Dowden.