2008 vice-presidential candidacy,

Since shortly following Biden's withdrawal from the presidential race, Obama had been privately telling Biden that he was interested in finding an important place for him in a possible Obama administration. In a June 22, 2008, interview on NBC's Meet the Press, Biden confirmed that, although he was not actively seeking a spot on the ticket, he would accept the vice presidential nomination if offered. In early August, Obama and Biden met in secret to discuss a possible vice-presidential relationship. On August 22, 2008, Barack Obama announced that Biden would be his running mate. The New York Times reported that the strategy behind the choice reflected a desire to fill out the ticket with someone who has foreign policy and national security experience—and not to help the ticket win a swing state or to emphasize Obama's "change" message. Other observers pointed out Biden's appeal to middle-class and blue-collar voters, as well as his willingness to aggressively challenge Republican nominee John McCain in a way that Obama seemed uncomfortable doing at times. In accepting Obama's offer, Biden ruled out to him the possibility of running for president again in 2016.

After his selection as a vice presidential candidate, Biden was criticized by his own Roman Catholic Diocese of Wilmington bishop over his stance on abortion, which goes against the church's pro-life teachings. The diocese confirmed that even if elected vice president, Biden would not be allowed to speak at Catholic schools. Biden was soon barred from receiving Holy Communion by the bishop of his original hometown of Scranton, Pennsylvania, because of his support for abortion rights; however, Biden did continue to receive Communion at his local Delaware parish. Scranton became a flash point in the competition for swing state Catholic voters between the Democratic campaign and liberal Catholic groups, who stressed that other social issues should be considered as much or more than abortion, and many bishops and conservative Catholics, who maintained abortion was paramount. The New York Times reported that Biden "departed from party doctrine on abortion rights, declaring that as a Catholic, he believes life begins at conception", but Biden said that he would not impose his personal religious views on others.

Biden's vice presidential campaigning gained little media visibility, as far greater press attention was focused on the Republican running mate, Alaskan Governor Sarah Palin. During one week in September 2008, for instance, the Pew Research Center's Project for Excellence in Journalism found that Biden was only included in five percent of the news coverage of the race, far less than for the other three candidates on the tickets. Biden nevertheless focused on campaigning in economically-challenged areas of swing states and trying to win over blue-collar Democrats, especially those who had supported Hillary Rodham Clinton.Biden attacked McCain heavily, despite a long-standing personal friendship; he would say, “That guy I used to know, he’s gone. It literally saddens me.” As the financial crisis of 2007–2008 reached a peak with the liquidity crisis of September 2008 and the proposed bailout of United States financial system became a major factor in the campaign, Biden voted in favor of the $700 billion Emergency Economic Stabilization Act of 2008, which passed the Senate 74–25.

On October 2, 2008, Biden participated in the campaign's one vice presidential debate with Palin. Polling from CNN, Fox and CBS found that while Palin exceeded many voters' expectations, Biden had won the debate overall. On October 5, Biden suspended campaign events for a few days after the death of his wife's mother. During the final days of the campaign, Biden focused on less-populated, older, less well-off areas of battleground states, especially in Florida, Ohio, and Pennsylvania, where polling indicated he was popular and where Obama had not campaigned or performed well in the Democratic primaries. He also campaigned in some normally Republican states, as well as in areas with large Catholic populations. Under instructions from the Obama campaign, Biden kept his speeches succinct and tried to avoid off-hand remarks, such as one about Obama being tested by a foreign power soon after taking office that had attracted negative attention. Obama strategist David Axelrod said that any unexpected comments had been outweighed by Biden's high popularity ratings. Nationally, Biden had a 60 percent favorability rating in a Pew Research Center poll, compared to Palin's 44 percent.

On November 4, 2008, Obama was elected President and Biden Vice President of the United States. The Obama-Biden ticket won 365 electoral college votes to McCain-Palin's 173, and had a 53–46 percent edge in the nationwide popular vote.