A former prosecutor, Harris, 59, appeared to get under the former president's skin with a series of sharp attacks, prompting a visibly angry Trump to deliver a stream of falsehood-filled retorts.
At one point, she brought up Trump's campaign rallies, goading him by saying that people often leave early "out of exhaustion and boredom."
Donald Trump and Kamala Harris sparred on politics and personality. (EPA PHOTO)
Trump, who has been frustrated by the size of Harris' crowds, said: "My rallies, we have the biggest rallies, the most incredible rallies in the history of politics."
He then pivoted to an unsubstantiated conspiracy theory claiming that Haitian immigrants in Springfield, Ohio, are "eating the pets" of residents.
"Talk about extreme," Harris said, laughing.
Harris also criticised Trump over his criminal conviction for covering up hush money payments to a porn star as well as his other indictments and a civil judgment finding him liable for sexual assault. Trump has denied wrongdoing and again accused Harris and the Democrats of orchestrating all of the cases without evidence.
Harris sharply criticised former president Trump for the state of the US economy. (EPA PHOTO)
Trump also repeated his false claim that his 2020 election defeat was due to fraud, called Harris a "Marxist" and asserted falsely that migrants have caused a violent crime spree.
With eight weeks to go before the November 5 election, and days until early voting starts in some states, the debate - the only one scheduled - presented both opportunities and risks for each candidate in front of a televised audience of tens of millions of voters.
The candidates opened the debate by focusing on the economy, an issue that polls show favours Trump.
Harris attacked Trump's intention to impose high tariffs on foreign goods - a proposal she has likened to a sales tax on the middle class - while touting her plan to offer tax benefits to families and small businesses.
"Donald Trump left us the worst unemployment since the Great Depression," Harris said, referring to his years as president from 2017-2021.
Unemployment peaked at 14.8 per cent in April 2020 and at 6.4 per cent when he left office. It was far higher in the Great Depression.
Trump criticised Harris for the persistent inflation during the Biden administration's term, though he overstated the level of price increases.
Trump and Harris exchanged barbs over the Israel-Gaza war. (AP PHOTO)
Inflation, he said, "has been a disaster for people, for the middle class, for every class."
Harris delivered a lengthy attack on abortion limits, speaking passionately about women denied emergency care and victims of incest unable to terminate their pregnancies due to statewide bans that have proliferated since the US Supreme Court eliminated a nationwide right in 2022. Three Trump appointees were in the majority of that ruling.
She also claimed Trump would support a national ban, an assertion Trump called a lie.
Trump, who has sometimes struggled with messaging on abortion, claimed falsely that Harris and Democrats support infanticide, which - as moderator Linsey Davis noted - is illegal in every state.
"As I said, you're going to hear a bunch of lies," Harris said.
Harris also sought to tie Trump to Project 2025, a conservative policy blueprint that proposes expanding executive power, eliminating environmental regulations and making it illegal to ship abortion pills across state lines, among other right-wing goals.
Trump retorted that he has "nothing to do" with Project 2025, though some of his advisers were involved in its creation.
The candidates also exchanged barbs over the Israel-Gaza war and the Russian invasion of Ukraine, though neither offered specifics on how they would seek to end each conflict.
