The first state to open its polling stations was Virginia at 6:00 am (1100 GMT).
A total of 12 states from Alabama to Alaska are holding primaries or caucuses on Tuesday, with frontrunners Hillary Clinton and Donald Trump hoping to finish off their challengers.
If Democrat Clinton and Republican Trump — an outspoken billionaire political neophyte who has unexpectedly tapped into a reservoir of conservative rage at conventional politics — win big, it could spell doom for their challengers.
With just hours to go before polls open, the duo made last-ditch appeals to supporters ahead of a day like few others on the calendar leading to the November election for the White House.
Trump’s Republican rivals, Senators Marco Rubio and Ted Cruz, were trying frantically to halt the real estate magnate’s march toward the nomination, seeking to unite the party against the man they see as a non-conservative political interloper.
Clinton meanwhile was riding high after thrashing rival Bernie Sanders in South Carolina over the weekend, securing an astronomical 86 percent of the African-American vote in her third win in four contests.
Should she win black voters by similar margins in places like Alabama, Georgia and Virginia, she should dominate there to become once again the inevitable candidate.
That was her status at the start of the campaign — before the rise of Sanders, a self-described democratic socialist.
She was leaving nothing to chance, traveling to multiple states Monday to urge a strong turnout.
Clinton also took aim at the increasingly hostile campaign rhetoric on the Republican side led by the brash real estate mogul Trump.
“I really regret the language being used by Republicans. Scapegoating people, fingerpointing, blaming. That is not how we should behave toward one another,” she told hundreds at a university in Fairfax, Virginia.
“We’re going to demonstrate, starting tomorrow on Super Tuesday, there’s a different path that Americans ought to take.”
Trump’s incendiary campaign has infuriated Republican rivals, including mainstream favorite Rubio who has intensified his personal attacks and stressed Trump would have trouble in a general election.
The Florida senator warned supporters in Tennessee that US media and Democratic groups will jump on Trump “like the hounds of hell” if he wins the nomination.
But Trump is clearly in the driver’s seat. He is leading in polling in at least eight of the 11 Super Tuesday states.
And a new CNN/ORC poll shows the billionaire expanding his lead nationally, earning a stunning 49 percent support compared to second place Rubio at 16 percent.
Cruz of Texas is third, at 15 percent, followed by retired neurosurgeon Ben Carson at 10 percent and Ohio Governor John Kasich at six percent.
Trump punched back against Rubio, calling him “Little Marco,” mocking him for sweating on the campaign trail and warning that Rubio could not stand up to strong men like Russian President Vladimir Putin.
Party of Lincoln
Trump’s inflammatory rhetoric, including accusing Mexico of sending rapists across the border, mocking women and the disabled and urging a ban on Muslims entering the country, would have been the undoing of a normal candidate.
But the 2016 cycle has been anything but normal, with a furious electorate keen to back an outsider who scorns the political establishment.
“I’m representing a lot of anger out there,” Trump told CNN.
“We’re not angry people, but we’re angry at the way this country’s being run.”
In the latest controversy, Trump came under withering criticism for not immediately disavowing the support of David Duke, who once led the Ku Klux Klan.
Rubio said Trump’s failure to promptly repudiate Duke, who has expressed support for Trump, makes him “unelectable.”
Some conservatives have said they will shun Trump if he is the nominee.
“This is the party of Abraham Lincoln,” said Senator Ben Sasse, accusing Trump of being a non-conservative plotting a “hostile takeover” of the party.
Trump supporters, Sasse told MSNBC, “need to recognize that there are a whole bunch of other people who say, if this becomes the David Duke/Donald Trump party, there are a lot of us who are out.”
If Trump sweeps the South, where many of the Super Tuesday races are taking place, it could be lights out for his Republican challengers.
Texas is the largest prize Tuesday, and Cruz is banking on winning his home state. He trails in nearly all other Super Tuesday states.
Almost 600 Republican delegates are up for grabs Tuesday, nearly half the 1,237 needed to secure the nomination.
Some 865 Democratic delegates are at stake, 36 percent of those needed to win.