A number of the Senate minority leader’s closest allies won’t be returning to the upper chamber next year, and the incoming senators replacing them aren’t likely to make Mitch McConnell’s stewardship of the party during the next Congress an easy one. 

Senators Portman and Burr — moderate Republicans with a combined 30 years of tenure in the Senate — will be replaced by President Trump’s hand-picked candidates. 

Mr. Portman, who negotiated the bipartisan infrastructure bill, will be replaced by author and venture capitalist J.D. Vance. Mr. Vance has embraced the former president and far-right members of the party like Congresswoman Marjorie Taylor Greene.

Mr. Burr will be replaced by Congressman Ted Budd, a representative with little legislative accomplishment who only received the former president’s endorsement after claiming the 2020 election was stolen. 

Senator Inhofe, a member of the chamber for nearly 30 years, announced his resignation in February, triggering a special election in Oklahoma coinciding with this year’s midterm elections. The victor, Congressman Markwayne Mullin, is another Trump choice who has denied the legitimacy of the 2020 presidential election. 

J. Miles Coleman of the University of Virginia Center for Politics told the Sun that these retirements will make the Senate GOP start to resemble the more unwieldy House Republican Conference. 

“To me, a perfect example of that has been the Tennessee delegation: Two of the more pragmatic Republicans, Bob Corker and Lamar Alexander … were replaced with Blackburn (a strident conservative in the House) and Hagerty (who won his seat in large part due to his association with Trump),” Mr. Coleman said via email. 

Messrs. Trump and McConnell have long had a fraught relationship, and in the nearly two years since the 2020 election, the former president has consistently called for the Kentuckian to be replaced as Republican leader. 

Mr. McConnell’s problems aren’t just confined to the incoming class of senators. He has also faced resistance from those with whom he currently works. Senator Johnson, who was just elected to a third term, also called for Mr. McConnell to be ousted as leader. 

As did Senator Braun, who is leaving the chamber to run for governor in his home state of Indiana. An open Senate seat there gives the anti-McConnell faction another chance to expand its ranks. Congressman Jim Banks, a conservative firebrand, will likely run. 

There are a few bright spots for Mr. McConnell. Senator Shelby, an influential committee leader, will be succeeded by his former chief of staff, 40-year-old Katie Britt. She defeated a far-right congressman, Mo Brooks, in the Senate primary, saving Mr. McConnell from an additional antagonist.

Mr. Coleman said that Ms. Britt will be a “fairly pro-McConnell vote.”

Last month, for the first time in his tenure, Mr. McConnell faced a leadership challenge. Senator Scott of Florida announced his bid for Republican leader in a letter to colleagues in which he calls for an end to the “status quo.”

Voters “are begging us to tell them what we will do when we are in charge. Unfortunately, we have continued to elect leadership who refuses to do that and elicits attacks on anyone who does,” Mr. Scott wrote. 

Of the 48 Republican senators who voted in the leadership contest, Mr. McConnell won 37. Mr. Scott received 10 votes and one senator abstained. The vote is done by secret ballot, but the lawmakers who have publicly admitted to voting for Mr. Scott  include Senators Cruz, Hawley, Braun, and Johnson, all of whom were elected in the years following the 2010 Tea Party wave. 

The challenges Mr. McConnell has faced from within his ranks will have implications for his potential successors as well. Senator Thune, currently the no. 2 Republican and a potential leader candidate, demurred on his own re-election bid for months as Mr. Trump sought someone who might challenge him in a primary. 

Senator Cornyn, Mr. McConnell’s former deputy and another potential leader candidate, faced backlash from conservative activists and senators over a bipartisan gun reform bill he negotiated following the shooting at Robb Elementary in his home state of Texas. That could complicate a potential run for Republican leader as a new generation of conservatives joins the upper chamber. 

Mr. McConnell is on track to be the longest Senate leader in American history. As he nears the end of his tenure, it has become apparent that whoever succeeds him will inherit a more unwieldy caucus than Mr. McConnell took over 16 years ago. 

“I’d expect Thune to work hard on cultivating relationships with those newer members,” Mr. Coleman said.