Obama heads into the showdown in Denver with a narrow lead in his bid to defy historic omens sown by a stubbornly sluggish economic recovery, and to become only the second Democrat since World War II to win a second term.
Republican Romney, down in almost all the key battleground states that will decide who wins the 270 electoral votes needed to win on November 6, seeks a sharp change of momentum in a race that seems to be slipping away.
The rivals will step up to podiums at the University of Denver in the Rocky Mountain state of Colorado, at 7:00 pm (0100 GMT) to clash over the economy and other domestic issues.
But veteran anchor Jim Lehrer, who will steer the debate for tens of millions of viewers at home, has leeway under rules thrashed out by the two campaigns to bring up other burning issues.
That means Obama, 51, could face a grilling on his administration's shifting account of the attack on the US consulate in Benghazi, Libya on September 11.
Romney, 65, a multi-millionaire former venture capitalist, could come under scrutiny over his complex offshore tax arrangements, which Democrats have highlighted to press the case that he is indifferent to middle class struggles.
Romney badly needs to reset the narrative of the election, after a secretly filmed tape emerged of him branding 47 percent of Americans as "victims" who pay no taxes and depend on government for handouts.
Obama and Romney, who have rarely met or spoken, have spent days in seclusion honing debate techniques, offensive parries and comebacks.
Ohio Senator Rob Portman has been playing the role of Obama in Romney's shadow debates and Democratic Senator John Kerry, the defeated 2004 Democratic nominee, has been standing in for Romney.
Asked by reporters Tuesday if he was ready, Romney replied: "I'm getting there."
Obama ignored reporters' questions about the debate as he ducked out of a plush Nevada resort to tour the Hoover dam.
Both sides have been indulging in the usual wild game of expectations setting, with Obama's team predicting Romney will fire off some pre-baked "zingers" at the president.
Republicans have praising Obama's debating skills to the skies, hoping that a stronger-than-expected Romney can emerge from the first showdown with the momentum to chew into the president's polling lead.
Several national polls released before the debate showed a tight race, with Obama ahead by a few points.
The new Wall Street Journal/NBC News poll gave Obama a lead among likely voters of 49 percent to 46 percent, consistent with a RealClearPolitics poll average showing the graying US leader up by 3.5 percent.
A Washington Post-ABC News poll out Monday gave Obama a slimmer 49 to 47 percent lead, but likely voters in swing states -- who are expected to decide the election -- sided with the president by 52 to 41 percent.
The president also led in Virginia, Ohio and Florida, which may prove decisive.
On the eve of the debate, the campaigns traded red meat, pouncing on perceived liabilities of the other side in a daily battle to win news cycles.
Several conservative media websites published stories and footage of a speech in 2007, in which a sermonizing Obama -- then a senator -- praised his controversial former pastor Jeremiah Wright.
The speech, which had been extensively reported before, shows Obama in a more hard-edged mood than he is usually seen, decrying slow federal responses to Los Angeles riots and Hurricane Katrina, which harmed the black community.
"Much of what we saw on our television screens 15 years ago was Los Angeles expressing a lingering, ongoing, pervasive legacy -- a tragic legacy out of the tragic history this country has never fully come to terms with," Obama said.
Democratic aides dismissed the tape as a "lame" attempt to dig up old stories, and it appeared unlikely that the issue of the fiery Wright, whom Obama repudiated in 2008, would emerge as a key campaign issue this year.
Republicans were meanwhile delighted by a verbal slip by Vice President Joe Biden, who said the middle class had been "buried" for the last four years.
Democrats said Biden was talking about how president George W. Bush's policies continued to hurt the middle class deep into Obama's term.
Romney's running mate Paul Ryan issued a scathing response.
"Unemployment has been above eight percent for 43 months. Our economy is limping along right now. Vice President Biden, just today, said that the middle class, over the last four years, has been 'buried.' We agree," he said.
Debates are often billed as decisive, but they rarely change presidential races.
Some incumbent presidents, however, including Gerald Ford in 1976 and George H. W. Bush in 1992, have stumbled and ended up losing in November, so Obama will have to be on guard despite leading in the polls.
