Justice Anthony M. Kennedy’s retirement announcement was less than a day old when liberal activists rallied on the steps of the Supreme Court on Thursday, invoking the names of two Republican senators who, they believe, hold the future of Roe v. Wade in their hands.

“Remember Susan Collins! Remember Lisa Murkowski!” Neera Tanden, president of the liberal Center for American Progress, exhorted the crowd. “If they claim to be pro-choice, choice is on the line with this decision.”

Ms. Collins, of Maine, and Ms. Murkowski, of Alaska, are powerful — and rare — creatures in Washington: moderate Republican women who favor abortion rights and are unafraid to break with their party. Their no votes helped sink the Republican repeal of the Affordable Care Act last year; both objected vociferously to a provision that would have stripped funding from Planned Parenthood Federation of America, the women’s health and reproductive rights organization.

Now, with President Trump’s pledge to nominate a “pro-life” jurist to replace the retiring Justice Kennedy, the senators are under pressure as never before. Much like Justice Kennedy, they are swing votes — not in a court case, but in a coming confirmation battle that will shape the Supreme Court, and American jurisprudence, for generations to come.

The math in the Senate tells the tale. With Senator John McCain, Republican of Arizona, undergoing cancer treatment, Republicans have the slimmest of majorities: 50-49. If every Democrat votes against a Trump nominee, it would take just one Republican defector to block confirmation. And with a filibuster no longer an option, Democrats are powerless to block a nominee on their own.

So within minutes of Justice Kennedy’s announcement on Wednesday, Democrats and their allies began looking toward Ms. Collins and Ms. Murkowski.

So did the White House. Ms. Collins and Ms. Murkowski were among a bipartisan group of six senators who met separately with Mr. Trump on Thursday night to talk about the court vacancy. Earlier Thursday, Ms. Collins said in an interview that she had taken a call from the White House counsel, Donald F. McGahn II, and that she urged him to look beyond the list of deeply conservative jurists that Mr. Trump has promised to pick from — a significant request, given that Senator Chuck Schumer of New York, the Democratic leader, has declared that Democrats will not back any nominee on that roster.

Mr. Schumer has also made clear that he will make the fate of Roe v. Wade, the 1973 landmark decision that established a constitutional right to abortion, the centerpiece of Democrats’ strategy to block any nominee they consider extreme. Ms. Collins, choosing her words carefully, suggested Roe would figure into her decision-making.

“I believe in precedent,” she said. “In my judgment, Roe v. Wade is settled law, and while I recognize that it is inappropriate to ask a nominee how he or she would rule in any future case, I would certainly ask what their view is on the role of precedent and whether they considered Roe v. Wade to be settled law.”

Both senators are well aware that, no matter how they vote, one side is going to be unhappy. Ms. Murkowski acknowledged feeling the weight of the moment.

“There’s pressure because of the gravity of such a nomination,” Ms. Murkowski told Politico. “I am not going to suggest that my opportunity as a senator in the advise-and-consent process is somehow or other short-cutted just because this is a Republican president and I’m a Republican.”

Senator Chris Murphy, Democrat of Connecticut, framed the situation for Ms. Murkowski and Ms. Collins this way: “This is a legacy vote. Very few people in the Senate, even those who’ve been here for a long time, will cast a more important vote than this.”

Liberal activists and Mr. Schumer have demanded that a nominee not be confirmed until after the November election, but Senator Mitch McConnell, the Republican leader, has promised a speedy process, with a confirmation vote by fall.

For Democrats, unified opposition will be difficult — especially in an election year when 10 Senate Democrats are up for re-election in states won by Mr. Trump. Three of those Democrats — Heidi Heitkamp of North Dakota, Joe Donnelly of Indiana and Joe Manchin of West Virginia — voted last year to confirm Justice Neil M. Gorsuch. So did Ms. Collins and Ms. Murkowski.

Since then, Justice Gorsuch has emerged as a consistent vote in the high court’s conservative bloc.

To say that tensions are high in the Senate around Supreme Court nominees would be an understatement. The wounds of 2016 remain raw and open. Democrats are still angry that Republicans, led by Mr. McConnell, blockaded President Barack Obama’s nominee, Judge Merrick B. Garland of the Federal Appeals Court here, by denying him a hearing — and giving Mr. Trump opportunity to put Justice Gorsuch on the court.

Ms. Murkowski sided with leadership then. But Ms. Collins broke ranks and called for Judge Garland to have a hearing — a moment she recalled on Thursday. “This is not a pleasant situation,” she said, referring to the Kennedy vacancy. “But it’s not strange to me.”

Neither Ms. Murkowski nor Ms. Collins face re-election this year, which gives them a measure of freedom in how they vote. Still, they are likely to face pressure back home. Eliza Townsend, executive director of the Maine Women’s Lobby, a women’s rights group, said her organization intended to step up its contacts with Ms. Collins.

“Maine people understand that this is for all the marbles,” she said. “This is a critical, critical moment.”

Both Ms. Murkowski and Ms. Collins have long been independent figures in the Senate. In 2010, when Ms. Murkowski ran for re-election, she lost in a primary to a Tea Party Republican. Instead of bowing out, she ran a write-in campaign — posing a challenge to voters who needed to know how to spell “Murkowski” — and won. The victory effectively freed her from party constraints.

Ms. Collins has a reputation for working across the aisle. In 2013, she led an effort among Senate women, including Ms. Murkowski, to put an end to that year’s government shutdown. As co-chairwoman of a bipartisan group called the “Common Sense Coalition,” she helped end this year’s shutdown as well.

Last week, she helped put together two ideological opposites, Senator Ted Cruz, Republican of Texas, and Senator Dianne Feinstein, Democrat of California, to work on immigration legislation.

Conservative advocates said Thursday that they were confident the two would confirm the president’s pick.

“We’ve seen from their statements that they both are very concerned about a judge that’s going to be fair, impartial and abide by the rule of law, and I think that’s exactly what we’re going to get: someone they both are just not comfortable with but very happy to vote for,” said Carrie Severino, chief counsel and policy director of Judicial Crisis Network, a conservative advocacy group.

With the Senate gone for its July 4 recess, Ms. Collins and Ms. Murkowski may get a little break. But once Mr. Trump names a nominee, the pressure will rise.

“These are two women who have been very clear, over many decades, that our constitutional right that protects women’s most important right of privacy — their right to reproductive rights — is important to them,” said Judith L. Lichtman, former president of the National Partnership for Women and Families, and a longtime Washington advocate for women’s rights. “And now they have a chance to prove it.”