The ABC News-hosted debate on Tuesday night takes place just eight weeks before the November 5 election, with both candidates locked in a tight race that could still easily swing in either direction.
Early voting will start in some states just days after the debate.
The encounter is particularly important for Harris, with opinion polls showing that more than a quarter of likely voters feel they do not yet know enough about her, in contrast with the well-known Trump.
The televised debate also offers Harris, a former prosecutor, a chance to make her case against Trump, whose felony convictions, outspoken backing for supporters convicted of the January 6, 2021, attack on the US Capitol and frequent falsehoods all offer plenty of fertile ground.
Presidential debates can transform the dynamics of an election race. (AP PHOTO)
It will be the first time the candidates have met and follows weeks of personal attacks on Harris by Trump and his allies that have included racist and sexist insults.
A similar outburst on stage could turn off undecided voters, according to John Geer, a politics professor at Vanderbilt University.
Trump's advisers and fellow Republicans have urged him to focus on illegal immigration and high prices, issues that play well with voters, and portraying Harris as too liberal for the country.
"There's no floor for him in terms of how low he will go, and we should be prepared for that," Harris said in a radio interview.
Presidential debates do not always move the needle, but they can transform the dynamics of a race.
President Joe Biden's faltering performance against Trump in June was so damaging that it eventually led him to abandon his campaign.
The candidates are effectively tied in the seven battleground states likely to decide the election, according to polling averages compiled by The New York Times.
Kamala Harris will attack Donald Trump on abortion and the right-wing blueprint Project 2025. (AP PHOTO)
"There is more for Kamala Harris to gain and more for her to lose," said Mitchell McKinney, a former adviser to the US Commission on Presidential Debates, since she remains somewhat of an unknown for many voters.
Viewers will be looking for where she stands on various issues.
But just as important, they will look to see how she handles herself against Trump.
Trump, by contrast, is already well defined.
"You're either for him or against him" at this point, McKinney said.
The 90-minute debate from 9pm (11am on Wednesday AEST) will take place at the National Constitution Center in Philadelphia.
There will be no live audience and microphones will be muted when it is not a candidate's turn to speak.
Donald Trump is expected to attack Kamala Harris on illegal immigration and inflation. (AP PHOTO)
A Harris campaign official said the vice-president was expected to hammer Trump on abortion and describe him as unfit to lead.
She is also expected to tout her plans to strengthen the middle class and lower costs for consumers.
Abortion has been a top issue for Harris and Democrats since 2022, when the US Supreme Court - powered by three Trump appointees - eliminated a nationwide right to the procedure in a broadly unpopular decision.
She has also sought to tie Trump to Project 2025, a conservative blueprint from the Heritage Foundation think tank that proposes expanding executive power, eliminating environmental regulations and making it illegal to ship abortion pills across state lines, among other right-wing goals.
Trump has offered shifting rhetoric on abortion while distancing himself from Project 2025, even though it has links to many of his former advisers.
Trump will tie Harris to the Biden administration's immigration policy, attacking them for record levels of migrant crossings before a recent spate of executive orders drove the numbers down dramatically.
He will also likely blame Harris for high consumer prices that have Americans feeling pessimistic about the economy despite strong job and wage growth.
