Grudge match
Clinton, 68, and Trump, 70, have regularly exchanged sharp insults, raising the prospect of a fiery grudge match. Trump frequently chides Clinton as "Crooked Hillary" and has called for her jailing for the email controversy. Clinton condemns Trump as temperamentally unfit for the White House.
Trump dominated the crowded Republican debates with rapid-fire attacks on his rivals, but he has no experience in a one-on-one debate setting that requires more prolonged discussion of issues.
Clinton has participated in many one-on-one debates on the national stage with Barack Obama during their 2008 battle for the Democratic presidential nomination and with US Senator Bernie Sanders in their Democratic nominating race earlier this year.
Clinton's camp has done its best to raise expectations for Trump.
"Getting through a debate while maintaining your demeanour and not becoming unhinged should not be the standard," Clinton communications director Jennifer Palmieri told reporters.
The role of moderator Lester Holt of NBC News has also come under scrutiny ahead of the debate, with the Clinton campaign and her Democratic supporters urging him to correct Trump if he makes false claims.
Trump has also tried to influence Holt and the moderators of the other showdowns with Clinton, saying the candidates should be the ones to correct the record.
But in a year when outsiders like Trump and Sanders have made a mark, Trump's best argument could be that he is a better agent of change than the former secretary of state and U.S. senator from New York, said Scott Reed, a veteran Republican operative who is now chief strategist for the U.S. Chamber of Commerce.
"He's got to draw the contrast between Trump as the candidate of change and Clinton as the candidate of more of the same," Reed said.