The 90-minute debate, hosted by Fox News anchor Chris Wallace at Case Western Reserve University and the Cleveland Clinic in Cleveland, will be broadcast and streamed live by major networks and cable news channels at 9 p.m. EDT.
Because of the COVID-19 pandemic, only about 100 people will attend the debate in person.
Wallace has selected six topics for the debate -- the COVID-19 pandemic, race and violence in U.S. cities, the Supreme Court, the integrity of the election, Trump's and Biden's records and the economy.
The list of topics provides a snapshot of a tumultuous election year that has seen more than 7 million people in the United States sickened by the novel coronavirus and more than 200,000 COVID-19 deaths.
Trump has faced substantial criticism for his response to the virus, particularly after Pulitzer Prize-winning journalist Bob Woodward wrote in his book, Rage, that the president understood the deadly nature of the disease in early February and "played it down" to the American public because he didn't want to "create a panic."
The president has criticized Biden for the federal response to the H1N1 pandemic while he was vice president under President Barack Obama as well as previous statements that he would institute another national shutdown to curb the spread of the virus, if necessary.
The year has also been marked by months of protests nationwide opposing police brutality and racial injustice brought on mainly by the police killings of George Floyd in Minnesota and Breonna Taylor in Louisville, Ky., as well as the police shooting of Jacob Blake in Kenosha, Wis., which left him paralyzed.
Trump responded to the protests by sending federal police to multiple cities, threatening to deploy active military forces and stating that he'd authorized police to arrest and prosecute anyone who vandalized statues or monuments on federal property, stating such actions could result in up to 10 years in prison.
Biden has generally expressed support for the protests but has regularly urged demonstrators to refrain from violence and vandalism.
On Saturday, Trump nominated conservative appeals court Judge Amy Coney Barrett to succeed late Associate Justice Ruth Bader Ginsburg on the Supreme Court after she died of cancer at age 87 on Sept. 18.
Trump's move to appoint Barrett has been controversial because of the proximity to the election. Senate Republicans blocked Obama's appointee four years ago on the grounds that it was too close to the election.
Biden has said the Senate should not act on Trump's appointment "until after the American people select their next president and the next Congress."
The integrity of the election has also come under scrutiny as Trump has repeatedly declined to commit to a peaceful transfer of power, if Biden wins, in addition to repeatedly denouncing mail-in voting as risky and fraudulent -- despite numerous studies that have refuted those claims.
Postmaster General Louis DeJoy has faced intense scrutiny over operational changes that have led to slowdowns in mail delivery.
The debate also comes as Democrats call for Trump to release his tax records amid New York Times reports indicating he didn't pay any federal income taxes in 10 of the 15 years before he became president and paid just $750 in 2016 and 2017.
"It is critical that every debate includes questions that ask the candidates what they would do to address climate change and environmental injustice," the letter states. "Without these topics, any discussion on the economy, racial justice, public health, national security, democracy or infrastructure would be incomplete."
Tuesday's debate is the first of three. The others are scheduled for Oct. 15 and 22.