Senator Bill Cassidy, Republican of Louisiana, said on Friday that he would support Todd Blanche’s nomination as attorney general, effectively saving the confirmation of President Trump’s pick after two other Republican senators said they would oppose him.

Mr. Cassidy, who lost his re-election bid to a Trump-backed challenger, said in a speech on the Senate floor that he had deep concerns about “apparent lawfare,” the phrase he has used to refer to the Justice Department’s targeting of the president’s political enemies.

But Mr. Cassidy said that after much consideration, he had come to believe that Mr. Blanche, who has served as the president’s personal lawyer, would be better positioned to push back against Mr. Trump’s norm-busting demands than an alternative.

“Mr. Blanche is not perfect, and he will tell you this,” Mr. Cassidy said. “But the choice is not between perfection and Mr. Blanche. It is between Mr. Blanche and another acting attorney general, who may not run the department effectively under President Trump.”

He announced his decision hours after Senator Lisa Murkowski of Alaska became the second Republican to oppose Mr. Blanche’s confirmation, joining Senator Susan Collins of Maine. That threw the nominee’s fate into doubt, given that he could not afford additional Republican defectors, and intensified attention on Mr. Cassidy,.

Ms. Murkowski said in a statement that she, too, harbored concerns over the “politicization” of the Justice Department. But the conclusion she reached was the opposite of Mr. Cassidy’s: She said that she feared that Mr. Blanche would “fail to check the worst impulses of this administration.”

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. Collins, who is running for re-election in a state that Mr. Trump lost in 2024, said on Tuesday that she would vote against Mr. Blanche over similar concerns. Given the continued absence of Senator Mitch McConnell, the Kentucky Republican who has been gone for nearly eight weeks because of illness, Mr. Blanche could 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.

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 Jan. 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’s 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 his election defeat in May, said his views about Mr. Trump did not factor into his decision about Mr. Blanche.

“I have a history with Mr. Trump,” he said, “but that history does not matter one bit.”