The policy-heavy, relatively sedate debate stood in stark contrast to last week's chaotic presidential showdown between Donald Trump and Democratic presidential nominee Joe Biden, which was marred by personal insults from both men.
Mr Trump's Covid-19 diagnosis, along with his age and that of Mr Biden, added weight to the debate, as both Mr Pence, 61, and Ms Harris, 55, sought to demonstrate they were capable of assuming the office if needed. Either Mr Trump, 74, or Mr Biden, 77, would be the oldest US president to be sworn into office if victorious in November.
However, Wednesday's confrontation, which saw the candidates separated by plexiglass barriers, seems unlikely to alter the dynamics of a race, that Mr Biden is winning, according to opinion polls. Both candidates evaded certain questions, stuck to talking points and avoided major gaffes. Indeed, the night's biggest talking point was not a policy, but came when a fly landed on Mr Pence's head.
Here, we take a look at how both candidates fared in the debate.
Mike Pence's highlights
In his strongest moments, Mr Pence delivered the kind of calm, reasoned points that the combative Mr Trump rarely offers.
He sought to counter Ms Harris's attacks on the White House's pandemic response by turning the focus to the economy and tax policy, saying: "On Day One, Joe Biden's going to raise your taxes."
The vice president also asserted that Mr Biden would ban fracking and embrace the Green New Deal, a massive environmental proposal backed by liberal Democrats.
"More taxes, more regulation, banning fracking, abolishing fossil fuel, crushing American energy and economic surrender to China is a prescription for economic decline", he said. "President Trump and I will keep America growing. The V-shaped recovery that's underway right now will continue with four more years of President Donald Trump."
With the virus sweeping through the highest levels of government and Mr Trump just days out of hospital after his own Covid-19 diagnosis , his deputy Mr Pence acknowledged "our nation's gone through a very challenging time this year".
But he added: "I want the American people to know, from the very first day, President Trump has put the health of America first." He also promised millions of doses of a yet-to-be-announced treatment before the end of the year.
Mike Pence's lowlights
The most talked about moment of the night came when a fly landed on Mr Pence's head .
The incident went unmentioned onstage, with Mr Pence and Ms Harris continuing to focus on the discussion of systemic racism in the justice system.
But as the insect took up residence on Mr Pence's white hair, the social media firestorm was immediate . It easily created more, well, buzz than nearly anything else that occurred.
"That's not on your TV. It's on his head," tweeted MSNBC's Rachel Maddow. "The fly knows," tweeted author Stephen King. Others joked about the creature perhaps getting stuck in hair spray — or possibly now being a prime candidate for coronavirus testing.
Democratic presidential nominee Joe Biden immediately got in on the act, tweeting a photo of himself clutching an orange flyswatter under the heading "Pitch in $5 to help this campaign fly." Moments later, he tweeted again, this time highlighting "Flywillvote.com," which took users to a website set up for his campaign to help supporters make plans to vote.
Mr Pence had spent much of the night shaking his head in response to Ms Harris' answers. But the vice president didn't appear to notice the fly's arrival. Despite his talking and normal body movements, the hot stage lights and those virus-fighting barriers, the fly was unperturbed. It finally flew away on its own.
Kamala Harris' highlights
Ms Harris condemned the killings of Breonna Taylor in Kentucky and George Floyd in Minnesota and spoke about the protests against racial injustice in policing that followed, which Mr Trump has portrayed as “riots” as he calls for law-and-order.
“We are never going to condone violence but we must always fight for the values that we hold dear,” Ms Harris said. “I’m a former career prosecutor. I know what I’m talking about. Bad cops are bad for good cops.”
The democratic candidate also hit out at Mr Trump's taxes. The New York Times reported last month the businessman president pays very little personal income tax but owes hundreds of millions of dollars in debt.
“It’d be really good to know who the president owes money to,” Ms Harris said.
“The one thing we know about Joe, he puts it all out there. He is honest, he is forthright. Donald Trump, on the other hand, has been about covering up everything.”
Kamala Harris lowlights
Ms Harris turned the coronavirus vaccine into a political football.
Asked about a potential vaccine, Ms Harris said she would only trust the word of scientists, rather than that of Mr Trump, who has promoted unproven treatments in the past.
"If the doctors tell us that we should take it, I'll be the first in line to take it, absolutely," she said. "But if Donald Trump tells us to take it, I'm not taking it."
Mr Pence fired back, accusing Ms Harris of undermining public confidence in vaccines. "I think it is unconscionable," he said. "Stop playing politics with people's lives."
Mr Pence sought to counter Ms Harris's attacks by turning the focus to the economy and tax policy, saying: "On Day One, Joe Biden's going to raise your taxes." Ms Harris responded by saying that Mr Biden has vowed not to raise taxes on anyone making less than $400,000 a year.
The vice president also asserted that Mr Biden would ban fracking and embrace the Green New Deal, a massive environmental proposal backed by liberal Democrats. Mr Biden, however, has rejected both of those positions.
What the experts are saying
There appeared to be no clear winners from last night's debate.
The BBC's North America reporter Anthony Zurcher said it was an "unmemorable affair". Both candidates had strong moments, as well as stumbles, he said. Given that Joe Biden has a clear lead in the polls, Mr Zurcher called the night a victory for his campaign.
CNN's Editor-at-large Chris Cilliza said both Pence and Harris were "more substantive and more effective" than either of the presidential candidates. The Independent's Washington Bureau Choef John T Bennett called the debate "a time-limit draw" and said it was time for Americans to "go vote".
However, conservative pundit Ann Coulter said that the liberal media calling the debate a draw meant that Mr Pence had "wiped the floor" with Ms Harris.
Meanwhile, President Trump also chimed in to say his VP had "won big".