Obama voted early Tuesday at an elementary school in Chicago with voters cheering him when he held up a validation slip.
"The journey ends," he told reporters later, "but voting with my daughters, that was a big deal."
McCain voted at a Phoenix, Arizona, church before heading to Colorado and New Mexico, two battleground states key to his hopes of an upset victory.
"I'm very happy with where we are," McCain told ABC television's "Good Morning America" in an interview hours before polls opened. "We always do best when I'm a bit of an underdog."
Later, McCain implored voters at a rally in Colorado to support him: "America is worth fighting for. Nothing is inevitable here," said the former Navy pilot and Vietnam prisoner of war. He was headed later to meet with volunteers in New Mexico before returning to Arizona to watch election returns.
His vice presidential running mate, Alaska Gov. Sarah Palin, case her ballot in her hometown of Wasilla, Alaska, Tuesday.
"Tomorrow I hope, I pray, I believe I will be able to wake up as vice president elect and get to work in a transition mode with president elect John McCain," said Palin, who helped McCain galvanize support among ardent conservative Republicans, but has come under criticism for her inexperience on a range of issues, including foreign policy.
While various polls had Obama enjoying a comfortable lead, the first term Illinois senator --who rocketed to the national spotlight from relative political obscurity -- was taking no chances, and continued his campaigning into Tuesday.
"It's going to be tight as a tick here in Indiana," Obama told volunteers in the Republican stronghold of Indiana, where some polls start to close at 6 p.m. (2300 GMT). "So the question is who wants it more."
Obama won the day's first contest, in two small New Hampshire towns where voters traditionally cast ballots shortly after midnight. Bush carried both towns in the last two elections.
The handful of votes there were the first of tens of millions expected to be cast before the end of the day.
An estimated 153 million voters were eligible, and in an indication of interest in the battle for the White House, 40 million of so had already voted by Tuesday. Turnout was heavy. In Virginia, for example, officials estimated nearly 75 percent of eligible voters would cast ballots.
The southern state, where no Democratic presidential candidate has won since Lyndon Johnson in 1964, is one of eight key battleground states that could determine the winner. The others include Florida, North Carolina, Pennsylvania, Ohio, Indiana, Missouri and Nevada.
Obama seemed to hold the edge in pre-election balloting, as officials reported that more Democrats than Republicans had voted in North Carolina, Colorado, Florida and Iowa. All four states voted for Bush in 2004.
While Obama's campaign voiced resounding confidence, the candidate had warned his supporters to take nothing for granted as the race depended on a relative handful of states that could go to either man.
Both the 47-year-old Obama, and McCain, a 72-year-old veteran senator, pledged to bring sweeping change to Washington and close the door on the two-term presidency of Bush -- whose approval ratings are near historic lows on the back of the Iraq war and, most recently, the U.S.'s faltering economy. The financial crisis has, for months, eclipsed the war as Americans' foremost concern.
But the two were divided by age, race and core political convictions. They were deeply at odds over how to fix the U.S.'s crumbling economy and end the 5 1/2-year war in Iraq.
Obama has argued that McCain would continue Bush's policies while the Republican counters that Obama is too inexperienced to lead.
The tug-of-war for battleground states is crucial as the American presidential election amounts to separate contests in 50 states and Washington, D.C.
At stake are 538 electors, with the winner needing to capture at least 270, half plus one. Electors are apportioned to the states roughly according to population.
Obama was favored to win all the states that Democrats captured in 2004, representing 251 electoral votes. Victories in just a few additional states could push Obama past the 269 threshold.
McCain, meanwhile, must hold as many Bush states as possible while trying to capture a Democratic stronghold, such as Pennsylvania in order to keep his hopes alive.
Despite Obama's lead in the polls, it remained to be seen whether some Americans would actually vote for a black man and make history in a country where, just a few decades ago, blacks were denied their right to vote in some states.
The final hours of Obama's campaign were bittersweet, with the young senator mourning the loss of his grandmother.
Madelyn Payne Dunham, 86, who died of cancer in Hawaii late Sunday.