The Senate majority leader is facing withering criticism from President Donald Trump -- who described him as "unpopular" -- and many conservative Republicans who blame him for failing to accomplish the party's top legislative goal despite years of promises and months of negotiations.
"We haven't given up on changing the American health care system, we are not going to be able to do that this week," a disappointed McConnell told reporters, as time ticked toward a deadline at the end of the month when the GOP will lose the ability to pass an Obamacare repeal bill on a party-line vote.
First, the McConnell-backed candidate in the runoff for an Alabama senate seat, Sen. Luther Strange, was defeated by a far-right conservative, Judge Roy Moore, who is highly critical of McConnell and his establishment bona fides.
"I'm now enemy No. 1," Moore warned McConnell in a recent fundraising message, a reflection of how difficult Moore could make things if he wins a seat in the McConnell-led chamber.
Conservative voices off Capitol Hill also gunned for McConnell. At a rally for Moore this week, the politically powerful former Trump adviser Steve Bannon blasted McConnell and made clear he wants him out
"Mitch McConnell and this permanent political class is the most corrupt and incompetent group of individuals in this country," Bannon declared.
Asked if a loss for Strange would negatively impact McConnell's reputation on Capitol Hill, conservative Alabama GOP Rep. Bradley Byrne said: "The Senate is such a clubby place I can't begin to tell you how it will affect him in the Senate."
But, he added, "House Republicans are already unhappy with the Senate. That's not a secret and I don't think this will make this any worse but it is indicative of broader unhappiness among the Republican electorate."
The second political challenge for McConnell came when Sen. Bob Corker, the two-term Republican from Tennessee and chairman of the foreign relations committee, who has been a McConnell ally and steady presence in the GOP conference, announced he would retire rather than run again
McConnell had urged Corker to stay on, Senate sources told CNN, and his decision to leave opens the seat to possible Democratic takeover, albeit in a reliably Republican state.
Before the repeal bill was officially ditched, the leader of a group of conservative GOP House members cautioned McConnell "all options" would be "on the table" to challenge McConnell if he didn't deliver on the Republican agenda.
"We would hope that the majority leader would listen to his constituents as much as we listen to ours throughout the states we represent," said Rep. Mark Walker, R-North Carolina, who chairs the influential and conservative Republican Study Committee. "We hope he can deliver on those promises but if not then we put all options on the table."
While Walker has no vote in Senate leadership elections, he can whip up political opposition and raise doubts about McConnell staying in power.
McConnell and House Speaker Paul Ryan, a Wisconsin Republican, are accustomed to rabble rousers on their right flanks. Both had promised drama-free governing that would try to pass spending bills on time and operate the mechanisms of government smoothly. But they also promised again and again to repeal Obamacare -- something anti-big government conservatives chaffed for -- perhaps without fully recognizing how difficult that might be.
Several Senate Republicans downplayed the notion McConnell's leadership post was endangered. It would fall to them to vote him out and there was little evidence they were prepared to take that step now.
"This isn't Mitch's fault. The fault that we got here is that we have too many people running around like a bunch of free-range chicken," said Sen. John Kennedy, R-Louisiana, about the convoluted health care negotiations that divided the moderate and conservative members of the Senate GOP conference.
"We have failed as a caucus. It's not just leadership, it's membership," said Sen. David Purdue, R-Georgia, when asked if McConnell should stay on as GOP leader.
Almost all Republican senators said it was time to turn to tax reform, the next big policy goal for Trump and congressional Republicans that they hope will unify the GOP across the spectrum and provide a major legislative accomplishment for voters before the midterm elections.
"There was no talk of changing leadership or anything else," said Sen. John Hoeven, R-North Dakota. "As far as our leadership structure, I don't hear anybody saying that's changing. The focus is all on getting taxes really done by the end of the year and continuing to work on health care."
Sen. Lindsey Graham, R-South Carolina, who co-authored and championed the bill defended McConnell.
"The leadership team has done everything we've asked them," Graham said.
One GOP senator who has clashed with McConnell in the past was asked if, considering the health care debacle, McConnell is still an effective leader.
"He certainly led us to the confirmation of (Supreme Court Justice Neil) Gorsuch," replied Sen. Ron Johnson, R-Wisconsin, in a sarcastic reference to what McConnell critics see as the only major accomplishment for Republicans since they've had unified control of Congress and the White House.
"Listen, these are very difficult issues. It's not easy herding cats. I honestly don't envy leadership their tasks," Johnson added.