President Donald Trump and his Democratic challenger, Joe Biden, are facing off in Nashville, Tennessee, more than three weeks after their first debate.
A representative of the Commission on Presidential Debates has a mute button to ensure each candidate has two full minutes uninterrupted to deliver opening answers on six major topics.
They opened the debate by sparring over the coronavirus pandemic.
Mr Trump insisted he had done a good job with the worldwide pandemic and said the country needs to “learn to live with it”.
Mr Biden shot back: “People are learning to die with it.”
Responding to unfounded allegations from Mr Trump that he has received funds from Russian sources, Mr Biden noted that he has released 22 years of taxes, which he says show “I have not taken a penny from any foreign source ever in my life”.
Pointing his finger at Mr Trump, Mr Biden asked: “What are you hiding?”
The two candidates took questions on how they would deter foreign interference in American elections.
US officials have reported that Russian hackers have targeted the networks of dozens of state and local governments in the United States in recent days, stealing data from at least two servers.
The president said that nobody has been tougher on Russia through sanctions and pushing for increased military spending by NATO than him.
Mr Biden said his son did nothing inappropriate while working for a company in Ukraine while noting the president was the one who got impeached for dealings with that country.
Mr Trump said Mr Biden’s son Hunter drew a large salary from a Ukrainian firm.
Mr Biden responded that the accusation had been investigated repeatedly and did not link him to any wrongdoing.
He also noted that the president was impeached for attempting to pressure the president of Ukraine to find potentially damaging information on his family.