Trump has been damaged by accusations that he made unwanted sexual advances toward women - which he denies - and concerns about his claims that the election will be rigged against him.
The debate at the University of Las Vegas Nevada on Wednesday gives the New York businessman perhaps his best remaining chance to sway the dwindling number of Americans who are still undecided about which way to vote at the November 8 election.
"This one is important if Trump is going to have any chance to get back into this race," said Republican strategist Charlie Black. "He's going to have to talk about issues effectively and not get down in the mud, and he needs to talk about jobs."
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Trump campaign manager Kellyanne Conway acknowledged that her candidate goes into the debate, which starts at 9pm EDT (1200 AEDT Thursday), as the underdog.
For Clinton, who leads polls and in most of the battleground states where the election will likely be decided, the 90-minute debate is a chance to make a closing argument on why she is the best suited to succeed President Barack Obama.
Both candidates are likely to attack each other's character.
Clinton has struggled to get past concerns about transparency raised over her handling of emails while she was secretary of state from 2009 to 2013.
"She needs to be able to answer the email question," Democratic strategist Bud Jackson said.
"She hasn't quite hit that nail on the head yet. She should do better this time. And she should expect the unexpected."
But Trump's troubles have loomed the largest after a video from 2005 was released showing him bragging about groping women.
This has prompted him to lash out at what he calls a political and media system rigged against him, an apparent bid to discredit the process before the election takes place.
Trump called the event an important opportunity to talk to voters.
The debate is to include discussions of debt and entitlements, immigration, the economy, the Supreme Court, foreign hot spots and fitness to be president.
Both candidates have invited guests who could be seen as provocative.
According to several media reports, Trump asked Obama's half-brother Malik, who supports the Republican, as well as the mother of one of the four Americans killed in the 2012 attacks in Benghazi, Libya, a focus of Republican criticism of Clinton.
Clinton's guests include Mark Cuban, the billionaire owner of the Dallas Mavericks basketball team and a frequent Trump antagonist.
