Senator Lisa Murkowski, Republican of Alaska, said on Friday that she would oppose Todd Blanche’s nomination as attorney general, further imperiling his chances of confirmation.

Ms. Murkowski, who is the second Republican senator to oppose President Trump’s pick for the job, said in a statement that she harbored concerns over the “politicization” of the Justice Department, and worried that Mr. Blanche would “fail to check the worst impulses of this administration.”

Given her stance and with Democrats uniformly against him, Mr. Blanche can likely not afford any other Republican defections and still be confirmed.

Ms. Murkowski cited the department’s handling of the release of the Epstein files, which Mr. Blanche oversaw, and the settlement agreement that Mr. Blanche negotiated in Mr. Trump’s lawsuit against the I.R.S., which included the creation of a $1.8 billion compensation fund that could have been used to pay Jan. 6 rioters.

“The country needs an attorney general who will check the worst impulses of this administration,” Ms. Murkowski said. ”I hope Mr. Blanche is able to achieve that, if confirmed, but I simply do not have confidence that will be the case.”

Ms. Murkowski’s statement came days after Senator Susan Collins, Republican of Maine, said she would vote against Mr. Blanche because of similar concerns.

Senator Bill Cassidy, a Louisiana Republican who has also expressed concern about Mr. Blanche’s nomination, has not yet announced his position.

If Senator Mitch McConnell, the Kentucky Republican who has been absent from the Capitol for nearly eight weeks because of illness, remains absent, Mr. Blanche can only afford to lose two Republican votes and still win a majority for confirmation.

Ms. Murkowski, Ms. Collins and Mr. Cassidy are the only three remaining Republican senators in office who voted to convict Mr. Trump on impeachment charges and remove him from office following the Jan. 6, 2021, assault on the Capitol.

Mr. Trump had urged Senate Republicans to swiftly confirm Mr. Blanche, and Senator John Thune of South Dakota, the majority leader, had hoped to bring his nomination to a vote before lawmakers left Washington for their August recess.

If Mr. Cassidy were to announce that he opposed Mr. Blanche’s confirmation, the Senate would likely delay the vote until September, leaving Mr. Blanche as acting attorney general, a post he has held since April. Mr. McConnell said in a statement on Thursday that he had been discharged from a rehabilitation facility but gave no date for returning to the Senate, saying that he would continue to convalesce at home over a coming five-week recess.

Mr. Blanche’s nomination has had a rough road. The Judiciary Committee delayed advancing it to the full Senate after two Republican senators, John Cornyn of Texas and Thom Tillis of North Carolina, raised questions about the $1.8 billion fund, which Mr. Blanche had said would not move ahead, and the extraordinary immunity from tax audits given to Mr. Trump and his businesses in his resolution of the I.R.S. lawsuit.

After days of negotiation, Mr. Blanche on Sunday night provided written assurances that the fund was dead and that the immunity for the president would be narrowed, and Mr. Cornyn and Mr. Tillis dropped their objections.

But in her statement, Ms. Murkowski said that she worried that the fund could too easily be restored after Mr. Blanche’s confirmation, a concern shared by many critics.

“I am also keenly aware that the Department’s nearly $2-billion dollar slush fund — which likely would have rewarded January 6 protesters — is only off the table because this nomination is pending and the Senate has leverage,” she said. “Once we vote, that will end, and there is no telling what the future holds.”

Mr. Blanche met privately with Ms. Murkowski and Mr. Cassidy on Wednesday in the Capitol to discuss his nomination.

Like Ms. Collins, Ms. Murkowski is a supporter of abortion rights. In announcing their opposition, both of them referenced Mr. Blanche telling anti-abortion groups that he would take a hard line in enforcing the Supreme Court decision overturning Roe v. Wade.

Mr. Cassidy, who has become more openly critical of the president since losing his re-election bid to a Trump-backed challenger, has told reporters in recent weeks that he is particularly concerned about the Justice Department potentially targeting the president’s political opponents.

He has specifically cited an investigation of Cassidy Hutchinson, a former White House aide who testified before Congress and implicated President Trump in the violence at the Capitol on Jan. 6, 2021. Her explosive testimony infuriated Mr. Trump.