Away from politics, Mr Biden’s personal tragedies unavoidably re-entered the spotlight as he ran for the presidency.
On December 18, 1972, just weeks after he first won a Senate seat, Mr Biden’s wife Neilia and one-year-old daughter Naomi were killed in a car accident.
Neilia’s car struck a tractor trailer while the family was out Christmas shopping. Mr Biden’s sons, Beau and Hunter, were badly injured but survived the crash. Mr Biden later remarried, having daughter Ashley with his wife Dr Jill Biden in 1981.
In August 2013, tragedy struck again when Beau, by then a politician himself talked of as a future presidential hopeful, was diagnosed with brain cancer. He died two years later.
In the first debate, Mr Biden vigorously defended Mr Trump’s attacks on his family, namely on the business dealings and drug issues of his son Hunter.
Later, Mr Biden talked emotionally about his son Beau, who died of cancer in 2015 after having served in Iraq. He attacked Mr Trump over a report, denied by the president, that he had referred to soldiers as “suckers” and “losers”.
Mr Trump said: “I don’t know Beau, I know Hunter.” The president then said Hunter was thrown out of the military for drug use. Mr Biden responded: “That’s not true. My son had a drug problem. He has overtaken it and I am proud of him.”
During that period, Mr Biden continued his duties as vice-president and shared emotional moments with Mr Obama, the man who picked him as a running mate in 2008.
Hunter Biden’s business dealings were pushed to the front of the campaign agenda by Mr Trump’s team.
The Trump campaign claimed that Mr Biden was implicated in inappropriate business activity while he was vice-president, which Mr Biden denied.
The Trump campaign staged a stunt aimed at grabbing the headlines moments before the second debate when a former business associate of Hunter gave a seven-minute statement to the press outlining new allegations.
Mr Trump brought up those claims on the debate stage in Nashville, Tennessee, calling Mr Biden “corrupt”. His rival shot back: “I have not taken a penny from any foreign source ever in my life.”
The president invited Tony Bobulinski, a former business associate of Hunter, to the debate.
Mr Bobulinski described how he and Hunter had tried to do business in China in 2017. “I’ve heard Joe Biden say he never discussed business with Hunter. That is false,” Mr Bobulinski alleged at one point.
The statement included a slew of allegations. Mr Bobulinski said he was handing devices over to the FBI to back up his claims.
The move had echoes of a debate in the 2016 campaign when Mr Trump gathered Bill Clinton accusers before facing his wife and then Democratic nominee Hillary Clinton.
Mr Biden insists, as he has throughout this year, that such stories are smears. He also called Rudy Giuliani, the former New York mayor and Trump ally who has pushed the claims, a “Russian pawn”.
Mr Biden went on the attack in the second debate by bringing up Mr Trump’s Chinese bank account, which came to light recently via The New York Times. Mr Trump said it had been closed, and shot back: “I don’t make money from China. You do. I don’t make money from Ukraine. You do. I don’t make money from Russia.” Mr Biden denied that.
Read more: As it happened: Blow-by-blow account of Donald Trump and Joe Biden’s second presidential debate
Tensions with Obama
Mr Biden recalls in Promise Me, Dad, his book about those years, how Mr Obama once shed tears for his son and offered to personally pay for the treatment if money was short.
The pair’s relationship, the most significant of Mr Biden’s political career, was so close in public that their “bromance” became a familiar joke before they left office.