Trump has called Biden a socialist puppet who wants to destroy the suburbs and "hurt God." Biden says Trump is a fraud whose failed leadership during the coronavirus crisis has "caused people to die."
Here's what you need to know:
WHEN & WHERE?
The first faceoff is being moderated by Fox News Channel's Chris Wallace, a tough interviewer. He had a contentious one-on-one sitdown with Trump in July, and the president tweeted last year that he thinks Wallace is "nasty & obnoxious." Biden has so far avoided Wallace altogether.
WHAT'S THE FORMAT?
There will be no opening statements. Trump will be at the podium on the right side of the stage looking at the audience with Wallace in the middle and Biden on the left.
The commercial-free broadcast will be split into six segments of 15 minutes each devoted to six topics selected by Wallace. Those topics are: the Trump and the Biden records; the Supreme Court; Covid-19; the economy; race and violence in American cities; and the integrity of the election.
Trump will get the first question. The candidates have 2 minutes to answer the first question in each segment. Trump and Biden will then have an opportunity to respond to each other, and the moderator will use the balance of the time in the segment for a deeper discussion, according to the event organizer, the Commission on Presidential Debates.
WHAT ABOUT COVID?
There will not be a traditional handshake (or even an elbow bump) between the candidates before the debate starts, the commission said. Trump, Biden and Wallace won't be wearing masks on stage.
The audience, which the commission said is being limited to a much smaller-than-usual 80 to 100 invited guests, will also be tested for the coronavirus ahead of the debate, as are all attendees.
The restrictions also mean there will be no post-debate "spin room," the crowded and chaotic place where campaign surrogates try to lay out arguments for why their candidate won.
The debate was originally scheduled to be held at the University of Notre Dame in Indiana, but the school withdrew as the host site in July, citing health concerns.
HOW CAN I WATCH?
It can be watched live on all the major TV networks, including ABC, CBS, CNN, C-SPAN, Fox, MSNBC and NBC.
NBC News NOW will provide free debate coverage beginning at 8 p.m. ET, available to stream live and on demand across OTT platforms, including Peacock, NBCUniversal's new streaming service.
C-SPAN will be streaming it on its YouTube channel, and many of the major networks will offer it on their apps. On radio, NPR will be airing the debate and will also have a livestream available online. People can also watch via subscription streaming services like Hulu with Live TV, Sling TV and fuboTV.
NBCNews.com will live-blog the debate, including fact-checks and analysis.
This year’s faceoff will be unique in that most Americans are still working remotely and not commuting to and from offices. That means more people are likely to be viewing from home as opposed to mobile devices while on the go.
WHEN'S THE NEXT ONE?
The lone vice presidential debate between Vice President Mike Pence and Sen. Kamala Harris of California is up next in Utah on Oct. 7. That will be followed by two more presidential debates — a town hall-style debate in Florida on Oct. 15 and the last, in Tennessee, on Oct. 22, will have the same format as the first, hosted by NBC's Kristen Welker.
Dareh Gregorian reported from New York, Ahiza Garcia-Hodges from San Francisco and Katie Primm from Cleveland.