The 90-minute televised debate, the first between a sitting president and a former one, will air at 9pm, eastern time (11am on Friday AEST), on CNN and is expected to draw a huge audience.
A record 84 million watched Trump's first debate in 2016 against Hillary Clinton.
Both men enter the debate in Atlanta with political vulnerabilities that present a mix of risk and opportunity.
The debate takes place far earlier than normal - more than four months before the November 5 election day - and against a backdrop of polls showing the two men in a dead heat.
The clash also arrives at a moment of profound polarisation and deep anxiety among voters about the state of American politics.
Two-thirds of voters said in a May Reuters/Ipsos poll that they were concerned violence could follow the election, nearly four years after a mob of Trump supporters stormed the US Capitol.
The first US presidential debate for 2024 will be broadcast by CNN. (AP PHOTO)
Trump, 78, will take the stage as a felon who still faces three criminal cases, including charges related to his efforts to overturn the 2020 election.
The former president, who has suggested he will punish his political enemies if elected, will need to demonstrate that he does not pose a mortal threat to democracy, as Biden asserts.
Biden, 81, is under pressure to avoid verbal stumbles and deliver a forceful debate performance after months of Republican assertions his faculties have dulled with age.
Both men have little room for error, with any slip-ups to be used as evidence of cognitive decline.
Aaron Kall, a University of Michigan professor and an expert on presidential debates, said this "might be the most highly anticipated and important" one ever, given the closeness of the race, the country's political polarisation and the potential for gaffes.
For Biden in particular, he said, a moment of confusion or forgetfulness would prompt "endless news cycles" about his age and refuel speculation about Democrats possibly replacing him.
The debate is a chance for Joe Biden to turn around his campaign fortunes, analysts say. (AP PHOTO)
While national polls show a tied race, Biden has trailed Trump in most battleground states and recently saw his financial edge erased after Trump was convicted in connection with hush-money payments made to a porn star.
"Biden needs a change in the status quo, and this debate is his best opportunity yet to do it," said Jacob Rubashkin, an elections analyst at the non-partisan website Inside Elections.
"Right now, voters are looking at this race more like a referendum on Biden than a choice election, and that's dangerous territory for him to be in.
"But in the debate he can drive home the contrast angle - and Trump will be in the spotlight as well."
Neither Biden nor Trump is popular, and about a fifth of voters say they have not picked a candidate, are leaning toward a third-party candidate or might sit the election out, the latest Reuters/Ipsos poll suggests.
Biden and Trump have made little effort to disguise their mutual dislike.
A lot of voters were repelled by Donald Trump's behaviour in the first debate in 2020. (AP PHOTO)
During their first debate in 2020, Trump aggressively talked over Biden in a performance that turned off many voters.
CNN will attempt to avoid cross-talk by muting the candidates' microphones when it is not their turn to speak.
The debate will also take place without an audience.
Biden advisers say he will emphasise Trump's role in threatening abortion access, portray him as a danger to democratic norms and remind voters of Trump's often chaotic 2017-21 term in office.
Trump will focus on Biden's stewardship of the southern US border in the face of record numbers of migrants crossing illegally as well as the economy, particularly inflation, while also questioning his world leadership at a time of war in Gaza and Ukraine.
The second and final debate is scheduled for September.
