The CNN instant poll found 59 percent of respondents thought Ms Harris had won the debate versus 38 percent for Mr Pence.
The two clashed over Donald Trump’s handling of the coronavirus pandemic, policing and racial justice and the economy.
Mr Pence aggressively attacked the suggestion American policing is institutionally racist.
He said: “This idea that America is systemically racist, that there’s implicit bias in law enforcement, is a great insult to the men and women who work in law enforcement.”
The event took place in Salt Lake City, Utah, with the candidates separated by perspex screens.
The CNN poll is a significant loss for Mr Trump who is currently trailing his Democratic Party rival Joe Biden and needs an election gamechanger.
During the debate Ms Harris accused Mr Trump and Mr Pence of downplaying the initial coronavirus outbreak.
She said: “Here’s the thing, on January 28th, the vice president and the president were informed about the nature of this pandemic.
“They knew and they covered it up. The president said it was a hoax.
“This administration has forfeited their right to re-election based on this.”
Mr Pence fired back commenting: “The difference here was that President Trump makes the American people to make the choices in the best interest of their health.”
On Tuesday Mr Trump returned to the White House from the Walter Reed military hospital where he was being treated for coronavirus.
During his three night stay the president was treated with remdesivir, which he widely praised, and a number of other drugs.
In a video posted on Twitter Mr Trump said: “I want everybody to be given the same treatment as your president. Because I feel great, I feel perfect.
“I think this was a blessing from God that I caught it. This was a blessing in disguise.
“I caught it, I heard about this drug, I said let me take it and it was incredible the way it worked.”