Commentators call it a clash of the titans: a 90-minute endurance test between Clinton the Democrat, arguably the most experienced US presidential candidate ever, and Trump the Republican, perhaps the least experienced nominee for a major party.
The outcome of this political show for the ages could shape the last six-week stint of an election that has deeply polarized the country and left Trump fighting to overcome allegations of bigotry and sexism.
Wall Street stocks tumbled Monday in anticipation of the first of three live, televised debates before the November 8 election.
A decisive win for Clinton could see her pull ahead. A strong performance from Trump could keep the vote competitive or even possibly see him pull out in front.
Hosted at Hofstra University on Long Island, a mere 60-minute drive from Manhattan and chaired by NBC Nightly News anchor Lester Holt, the debate may attract an audience closer to the size of the Super Bowl when it kicks off at 9:00 pm (0100 GMT Tuesday), beamed live around the country.
The questions will revolve around three themes: "America's direction, achieving prosperity, and securing America."
Both candidates, the most disliked US presidential rivals in contemporary history, have spent days furiously prepping and honing which strategy they believe will inflict maximum damage on the other.
- Sweet spot -
Clinton, 68, is nothing if not experienced with four decades of public service tucked under her belt -- a veteran of 34 primary debates, having run and lost for president in 2008 against Barack Obama.
"When the spotlights are at the brightest and the pressure is the most intense, that's when she brings her A-plus game," said Clinton running mate Tim Kaine.
Trump, the 70-year-old maverick billionaire, has refused to play by the rules. He has never held public office but stormed through the primaries, crushing his 16 opponents with a populist, say-it-how-it-is message that has resonated among Americans fed up with establishment politicians.
According to a recent Washington Post/ABC News poll, 53 percent of Americans voters do not believe that Trump is qualified to be president, lacking the temperament and knowledge.
The Republican Trump is unrivalled at hogging the limelight, but considered weak on policy.
But while Clinton is masterful when it comes to policy details, she suffers from perceptions that she is untrustworthy and dishonest.
And Trump's campaign manager Kellyanne Conway says for all Clinton's proficiency it has not translated into campaign success.
"She's smart, but this isn't her sweet spot," she told MSNBC, calling her boss "a natural debater" by comparison.
"I have been in politics for 28 years," she said. "And I think Donald Trump has gifts and skills that sometimes escape typical politicians."
- Polls tied, stocks tumble -
Monday's target will be the estimated nine percent of American voters who are still undecided. Can the Democrat win their minds, if not their hearts? Can Trump persuade them that he has the gravitas to lead?
Clinton will no doubt aim to seize on Trump's toxic campaign trail rhetoric, using his words to paint her rival as a divisive demagogue.
But if Trump remains disciplined and focuses on issues, he could earn credibility among college-educated whites, according to veteran Democratic campaign strategist Joe Trippi.
"I do expect Donald Trump to be more genteel and a calmer force tonight, and I expect her to try to bait him out," Trippi told Fox News.
Stocks skidded on Wall Street with the Dow Jones Industrial Average dropping 0.9 percent to 18,094.83 amid unease over the debate.
The latest opinion polls have Clinton and Trump virtually tied: 41 percent each according to the Washington Post-ABC poll and 43 for Clinton to Trump's 42 percent according to Quinnipiac University.
Clinton's campaign has expressed concerns of being held to a double standard, saying the bar is higher for her while Trump stood to win praise for a merely adequate performance.
"All that we're asking is that if Donald Trump lies, that it's pointed out," Clinton campaign manager Robbie Mook told ABC.
Trump has already stated that he does not believe Holt's role as moderator is to police each candidate.
Obama, who is likely to be working in the White House with the debate "on in the background," believes Clinton needs to show Americans what motivates her to want to be president, spokesman Josh Earnest said.
"He obviously believes that she's got a strong case to make," Earnest told reporters.