Here's a wrap-up of some of the key moments from the debate:
The coronavirus pandemic will remain front and centre
The coronavirus pandemic will naturally be the most defining issue of the 2020 election.
It was the first topic posed to each candidate, and prompted some emotive responses.
Criticising the Trump administration's record, Ms Harris asked the American people a series of questions: "How calm were you when you were panicked about where you were going to get your next roll of toilet paper? How calm were you when your kids were sent home from school and didn't know when they could go back? How calm were you when your children couldn't see your parents because you were afraid that they could kill you?"
Mr Pence responded: "There is not a day that's gone by that I haven't thought of every American family who has lost a loved one. And I want every American to know that you'll be in our hearts and in our prayers."
Mike Pence did not commit to a peaceful transfer of power
Mr Pence sidestepped a question about whether President Donald Trump would commit to a peaceful transfer of power if he lost the election.
"If we have a free and fair election, we know we’re going to have confidence in it, and I believe in my heart that President Trump will be re-elected for four more years," he said.
The Trump administration continues to defend the Rose Garden event
Mr Pence defended Mr Trump's decision to nominate Judge Amy Coney Barrett to the Supreme Court at a Rose Garden ceremony on 26 September where there was no social distancing.
The event has been linked to several members of the Trump administration subsequently testing positive for COVID-19.
Mr Pence said many of the people who attended the event "actually were tested for coronavirus," before quickly moving on.
Supreme Court picks will be a recurring issue
Mr Pence pressed Ms Harris to answer whether a Biden administration would “pack” the Supreme Court by adding liberal justices if they win the election.
“Are you and Joe Biden going to pack the court if Amy Coney Barrett is confirmed? Are you going to pack the court?” he asked. “Your party is actually openly advocating adding seats to the Supreme Court, which has had 9 seats for 150 years, if you don’t get your way.”
Mr Pence added that the threat from Democrats is a “classic case of ‘if you can’t win by the rules, you change the rules.”
Mr Harris did not answer the question directly, even as Mr Pence continued to push for an answer. Mr Biden has also side-stepped the question in recent weeks - suggesting we could see it revisited over the coming weeks.
Kamala Harris refuses to 'be lectured' on race relations
When each candidate was asked about America's justice system, Ms Harris was at her most passionate as she slammed the President for refusing to condemn white supremacists.
Mr Pence responded saying he trusted the justice system and suggesting it was insulting to America's police officers to imply the country was racist.
"I will not sit here and be lectured by the vice-president on what it means to enforce the laws of this country," the former San Francisco prosecutor and California Attorney-General replied.