Vice-President Joe Biden and Republican Paul Ryan, a Wisconsin congressman, will clash for 90 minutes in Danville, Kentucky.
Democrats are hoping to change the campaign narrative after what was widely seen as a poor performance by President Barack Obama last week.
Barack Obama said on Wednesday he had been “too polite” to his rival, Mitt Romney.
The Obama campaign has since accused Mitt Romney, a Republican former business star and Massachusetts governor, of shifting his policy positions and of lying during their meeting in Denver, Colorado last week.
Thursday’s debate will be moderated by Martha Raddatz, senior foreign affairs correspondent for ABC News, and will cover both domestic and foreign policy.
It is set to begin at 21:00 EST at Centre College, a small liberal arts university about 80 miles from the city of Louisville.
The debate will be split into nine 10-minute segments.
The two vice-presidential candidates are tasked with keeping their respective campaigns competitive, as new polls suggest Barack Obama’s lead in several key swing states has been somewhat erased by Mitt Romney.
An NBC/Wall Street Journal poll released on Thursday showed Mitt Romney making gains in three states said to be essential to his presidential hopes.
The two candidates are virtually ties in Florida and Virginia while Barack Obama still leads in Ohio, but by a decreased margin. The Romney campaign has added extra campaign stops in Ohio in the coming weeks, aware that no Republican has ever won the White House without winning Ohio.
Also on Thursday, a New York Times/CBS News poll suggested that likely voters in Colorado, Virginia and Wisconsin – all states “in play” on 6 November – gave Mitt Romney stronger marks for leadership than previously.
However, the new poll showed no sharp movements in support for either candidates.
Joe Biden, 69, is known for his frank but folksy manner and foreign policy experience, while Paul Ryan, 42, is known as the Republicans’ budget hawk, serving in Congress for 14 years.
Both have kept lower profiles in the past week as they prepared for the debate.
“Joe just needs to be Joe,” Barack Obama told ABC News on Wednesday.
“Congressman Ryan is a smart and effective speaker. But his ideas are the wrong ones.”
The president played down the importance of his own first debate performance, saying: “What’s important is the fundamentals of what this race is about haven’t changed.”
Senior Obama adviser David Axelrod told CBS on Thursday that he believes “the big challenge for [Biden] is to pin Congressman Ryan down”.
“Right now the Romney campaign is running away from some of their positions like unwanted stepchildren.”
Mitt Romney expressed confidence in his running mate at a campaign stop in Ohio: “I think Paul Ryan will do great.”
The Wisconsin representative himself said he was not intimidated by Joe Biden.
“Joe Biden’s one of the most experienced debaters we have in modern politics,” Paul Ryan told reporters.
“But the Achilles’ heel he has is President Obama’s record.”
The debate is expected to focus on the federal budget plans Paul Ryan put forward as the chair of the House budget committee.
While the Obama campaign has sought to portray Paul Ryan’s place on the Romney ticket as an endorsement of the Ryan plan, the Romney campaign has worked to play down that impression.
“You have to remember that there is [a] Romney-Ryan ticket and there’s one presidential candidate,” Mitt Romney adviser Kevin Madden said.
“So the focus again will be on what Governor Romney’s plan is for reforming Washington.”
Joe Biden is said to have studied Paul Ryan’s most recent budget plan during his debate preparations.
The event is not expected to draw the approximately 70 million people who watched four years ago when Joe Biden debated Republican vice-presidential candidate Sarah Palin.
That debate did little to change the 2008 campaign but helped Sarah Palin after a series of disastrous interviews.
“Normally vice-presidential debates are good political theatre and sort of interesting from a talent scout standpoint, as you evaluate the up-and-comers on the political stage,” Alan Schroeder, author of a book on presidential debates, told the Associated Press.
“But this year could be different because of the negative reviews of Obama’s performance. That heightens expectations for this second debate.”
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