Biden, 81, and Trump, 78, will be under pressure to display their command of issues and avoid verbal stumbles as they seek a breakout moment in a race that opinion polls suggest has been deadlocked for months.
The 90-minute televised debate, the first between a sitting president and a former one, will air at 9pm ET (11am AEST on Friday) on CNN and is expected to draw a huge audience.
A record 84 million watched Trump's first debate in 2016 against Hillary Clinton.
The contest between President Joe Biden and former president Donald Trump is a rematch of 2020. (AP PHOTO)
The debate takes place far earlier than normal - more than four months before the November 5 election day.
It comes at a moment of profound polarisation and deep-seated anxiety among voters about the state of US 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.
Trump will take the stage as a felon who still faces a trio of criminal cases, including to his efforts to overturn the 2020 election.
The former president will need to convince undecided voters that he does not pose a mortal threat to democracy, as Biden asserts.
Biden arrived in Atlanta on Thursday afternoon under intense pressure to deliver a forceful performance after months of Republican assertions his faculties have dulled with age.
Ahead of the debate, Biden's campaign released a video featuring former Trump aides saying they would not support him this time.
"Take it from the people who know Donald Trump best - he is unfit to be president," Biden said on X.
On his Truth Social platform, Trump called Biden "a threat to the survival and existence of our country itself!"
Independent candidate Robert F Kennedy Jr., who did not qualify for the debate, was due to host his own event on X at the same time.
CNN will attempt to avoid cross-talk by muting the candidates' microphones when it is not their turn.
The debate will take place without an audience and neither candidate is allowed to bring notes or props although they will have a pen and paper.
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 2017-2021 term in office.
Trump will focus on the high levels of inflation and record numbers of migrants who have entered the country illegally under Biden's watch, and will also question his world leadership at a time of war in Gaza and Ukraine, Trump advisers said.
The White House Correspondents' Association said on Thursday CNN had rejected multiple requests to include White House pool reporters inside the studio during the debate.
The press pool, made up of representatives of major news organisations, accompanies the president on foreign and domestic trips and normally has access to any event where he speaks or appears in public, with the goal of keeping the US public informed.
It is extremely rare for them to be barred from an event in the United States.
"WHCA is deeply concerned that CNN has rejected our repeated requests to include the White House travel pool inside the studio," Kelly O'Donnell, president of the White House Correspondents' Association, said in a statement.
"The pool is there for the 'what ifs?' in a world where the unexpected does happen," she said, and to provide "context and insight by direct observation and not through the lens of the television production".
These reporters are there to see what is said and done when the microphones and cameras are off, and provide independent observation, she wrote, with duties "separate from the production of the debate as a news event".
