Democratic front-runner Hillary Clinton claimed victories in Georgia and Virginia, while rival Bernie Sanders won his home state of Vermont in Super Tuesday elections on the biggest day of the primary campaign.
Donald Trump won the Republican primary in Georgia, while other races were too close to call.
Clinton and Trump were pressing for sweeping victories that could distance them from their party rivals and move them closer to a November presidential election showdown.
Nominating contests were being held Tuesday in 12 of the 50 US states.
Trump, the brash billionaire and reality TV star, has stunned the Republican political establishment by winning three of the first four contests, seizing on the anxieties of voters angry at Washington and worried about terrorism, immigration and an uncertain economy. Using simple terms, and often coarse language, he has soared to the top of polls with his pledge to "make America great again."
Republican officials, fearing a Trump sweep, have been lashing out at his temperament and command of the issues in the hours before voting began.
"You've got a con man and a bully who is moving forward with great speed to grab the party's mantle to be its standard bearer," Norm Coleman, a former senator who backs Marco Rubio, said. "That's almost incomprehensible."
Clinton, once seen as the all-but-inevitable Democratic nominee, has contended with an unexpectedly strong challenge from Sanders, a senator and self-described democratic socialist. But Clinton, like Trump, had also won three of the first four races, and a landslide victory in South Carolina on Saturday bodes well for prospects in important southern states due to her overwhelming support among black voters.
Candidates are vying to win delegates who will vote for them at the parties' conventions in July. For Republicans, 595 delegates were at stake, nearly half of the 1,237 needed for the nomination. Democrats were allocating 865, delegates more than one-third of the 2,383 needed to become the nominee.
Tuesday's vote was critical for the two leading Republicans vying to be Trump's main challenger: Ted Cruz, a firebrand conservative senator from Texas, and Rubio, a Florida senator who has become the favourite of much of the Republican establishment.
Both senators have launched furious verbal attacks on Trump in recent days, but some in the party establishment fear the anti-Trump campaign has come too late.
Cruz once saw the Southern states that vote Tuesday as his opportunity to stake his claim to the nomination, given their large evangelical Christian populations, only to see Trump pick up a sizable segment of evangelicals. Now the Cruz campaign's future hinges on a victory in his home state of Texas, the biggest prize up for grabs.
Rubio's goal is even more modest. He's seeking to stay competitive in the delegate count and hoping to pull off a win in his home state of Florida on March 15.
Even before the results started flowing in, Trump was calling for Rubio to quit the race if he didn't win anywhere on Tuesday.
"He has to get out," he told Fox News. "He hasn't won anything."
Ohio Governor John Kasich and retired neurosurgeon Ben Carson remain in the race, but neither is expected to be a major factor at Super Tuesday.
Republicans spent months largely letting Trump go unchallenged, wrongly assuming that his populist appeal with voters would fizzle. Instead, he's appeared to only grow stronger, winning states and drawing support for some of his most controversial proposals.
In six of the states voting Tuesday, large majorities of Republican voters said they supported a proposal to temporarily ban all non-citizen Muslims from entering the United States, an idea championed by Trump.
Republicans fear Trump will damage their prospects of recapturing the White House after Barack Obama's two terms. The worries appeared to grow after Trump briefly refused to disavow the apparent support of a former Ku Klux Klan leader, David Duke, during a television interview. Trump later said he had not understood the TV interviewer and he did repudiate Duke.
The disarray among Republicans comes as Clinton, seeking to become America's first female president, has tightened her grip on the Democratic race. She has increasingly turned her attention away from Sanders and on to Trump, casting herself as a civil alternative to the insults and bullying that have consumed the Republican race.
"What we can't let happen is the scapegoating, the flaming, the finger pointing that is going on the Republican side," she told voters in Massachusetts. "It really undermines our fabric as a nation."
Sanders, who has energised young voters with his call for a political revolution, was seeking to stay close to Clinton in the South and pick up victories in other states including Minnesota in addition to Vermont. But he faces tough questions about whether he can rally minorities who are core Democratic voters.
Democrats were voting in 11 states and American Samoa; Republicans were voting in 11 states.