The 90-minute face-off at Hofstra University in Hempstead, New York, will be the first of three televised debates between the two United States presidential nominees.
The debate will be divided into six segments of 15 minutes, each on a different topic.
The candidates will have two minutes at the beginning of each topic to respond, and then they will debate each other.
American University professor and former White House speechwriter Eric Schnure says history shows the debates are important.
"There are defining moments in a lot of campaigns, and, if you think about it, presidential campaigns go on for a long time, from when someone announces a candidacy, through a nomination, through election day. I mean, you're talking a process that's years. But despite how long they are, there are only three moments where voters can look at candidates from two major parties next to each other onstage, head-to-head, face-to-face for the first time, and voters can make those decisions in real time."
The first televised US presidential debate was between Democrat John F Kennedy and the then Republican vice president, Richard Nixon.
"The candidates need no introduction. The Republican candidate, Vice President Richard M Nixon, and the Democratic candidate, Senator John F Kennedy ... "
Television viewers are said to have judged Senator Kennedy the winner, and he went on to win the election.
One of the biggest gaffes made on the debates was in 1976.
Senator Gerald Ford had succeeded Richard Nixon as president after the Watergate scandal, and he was closing the gap against Democratic contender Jimmy Carter.
Until this happened:
(Ford:) "There is no Soviet domination of Eastern Europe, and there never will be under a Ford administration."
(Moderator:) "Did I understand you to say, Sir, that the Russians are not using Eastern Europe as their own sphere of influence and occupying ... ?"
Analysts say the debates offer a big opportunity for both candidates to appeal to voters who have yet to commit to either of them.
And the latest polls show Ms Clinton holding only a four-percentage-point advantage over Mr Trump.
With just six weeks before the November 8th election, Eric Schnure, at the American University in Washington, says there is a lot at stake.
"This debate coming up, it's a different animal. It's not necessarily a test on who has better ideas, who knows the issues better, who has more experience. In a way you can wipe a lot of that off the table, and it's a test of who's more cool, calm and collected. And I think that's what makes it for such great television."
Millions are expected to tune into the debate.
This undecided voter says the entertainment is part of the appeal for watching.
"Not to sound negative or anything, I think it's because it's just one big joke, and everybody ... everybody wants to get in on it, you know? Everybody wants to see what's going on in America, and, you know, at this point, it's just all craziness, you know, so ... That's why I want to see it, because it's all just ... it's funny, it's funny to me."
