The eyes of the world will be on the 81-year-old's solo appearance at a NATO summit in Washington as concerns over his age and health spark growing calls in his Democratic Party for him to step aside.
The White House has dubbed it a "big boy" press conference, and Biden will be under close scrutiny to show he can handle a rare unscripted moment in his presidency.
Any missteps by Biden at the event -- which was delayed by an hour to 6.30 pm (2230 GMT) -- could turn the trickle of Democrats who have so far urged him to abandon his 2024 election bid into a flood.
The dam appeared to be breaking on Wednesday when Hollywood actor and Democratic supporter George Clooney called on Biden not to stand, and party grandee Nancy Pelosi stopped short of backing him.
Around a dozen Democratic members of the House of Representatives have now openly urged the man who beat Trump four years ago to drop out, along with one Democratic senator.
A new poll released on Thursday showed more than half of Democrats say Biden should end his bid for a second term, and two thirds of Americans believe he should quit the race.
But the debate did not seem to have moved the overall battle with Trump, with the former president and the incumbent remaining in a dead heat on 46 percent, according to the Washington Post-ABC News-Ipsos survey.
Despite that, Biden now faces what CNN called the "most high-pressure presidential news conference in modern history", exactly two weeks after his stumbling debate performance ignited a firestorm of concerns about his age, health and mental acuity.
Top House Democrat Hakeem Jeffries said on Thursday he was speaking with each of the party's representatives, adding that they would then "convene as a leadership team and figure out the next step."
The once-talkative Biden has given fewer news conferences than his predecessors, and recent ones have only been with foreign leaders, restricted to two questions each.
Coupled with a lack of interviews, it has led critics to accuse the White House of shielding the effects of age on America's oldest president.
White House Press Secretary Karine Jean-Pierre has repeatedly promised Thursday's "big boy press conference" -- a phrase first used by a journalist that she has since adopted -- will feature multiple questions.
Biden has called his debate meltdown a "bad night", blaming it on a cold and jet lag.
But Clooney tried to torpedo the narrative that it was a one-off, saying it was "devastating" to admit but the signs were also clear at a June 15 fundraiser in Los Angeles he hosted.
Biden has insisted that he is committed to running in November, and with the Democratic party primary votes under his belt there is no real way of forcing him out.
His campaign fought back Thursday with a new ad campaign on the last day of the NATO summit portraying Trump as a "lap dog" of Russian leader Vladimir Putin.
NATO allies have also been seeking reassurance about Biden's leadership abilities and over their fears that a return of the isolationist, Putin-praising Trump could spell trouble for the alliance.
Biden separately hailed "significant progress" in fighting inflation -- one of his other political weak spots -- after consumer figures came in cooler than expected Thursday.
Should Biden drop out, Vice President Kamala Harris is the frontrunner to replace him but any move would have to be before the Democratic convention in Chicago in August.