Romney thumped his main rival Rick Santorum in Maryland and the US capital Washington, and was expected to win a tighter but more important race in Wisconsin, US media projected, in a pivotal night for the frontrunner.
"Thank you to Wisconsin, Maryland and Washington, DC. We won them all! This really has been quite a night," Romney told euphoric supporters in Milwaukee, Wisconsin.
But impressive as the Romney victories were, Santorum insisted the Republican race to see who will challenge President Barack Obama in November was merely at "halftime," and that he would carry on at least into May, when there will be a series of primaries in states more favorable to Santorum.
"The clock starts tonight," Santorum told supporters in his home state of Pennsylvania, which votes later in April.
"We've got three weeks to go out here in Pennsylvania and win this state. And after winning this state, the field looks a little different in May," he said.
But Santorum must feel the sting of a loss in Wisconsin, where he campaigned heavily over the last week. With nearly half of voting precincts reporting, Romney had 42 percent of the vote to Santorum's 38 percent.
Santorum virtually ignored the other two contests in the hope of snagging a victory in the Midwest, where the arch-conservative has fared far better than in the more moderate Northeast.
In Maryland, Romney was on 48 percent to Santorum's 30 percent, with former House speaker Newt Gingrich and Texas congressman Ron Paul far off the pace, according to partial results.
The trifecta puts Romney beyond the halfway mark in the march to getting the magic number of 1,144 delegates needed to be crowned the Republican flag-bearer at the party's national convention in August.
Tuesday appeared to mark the start of a new phase in Romney's campaign, as he turns his full attention to challenging Obama in November.
The Republican establishment has been steadily coalescing behind the former Massachusetts governor, and he is already acting like the nominee, training his political fire on Obama's "government-centered society" and no longer mentioning his Republican rivals while on the campaign trail.
Obama on Tuesday also essentially helped kick off a new phase in the general election campaign, rebuking Romney by name in a speech and calling him to account for supporting what the Democratic president sees as a "radical" budget passed by congressional conservatives last week.
Obama accused Romney of championing cutthroat "social Darwinism" that neglects the middle class and favors the wealthy, and said the Republican candidate is seeking to institute such a budget on "day one of his presidency."
Romney launched a spirited retort, signalling his eagerness to square off with Obama.
"This is a president who so misrepresents the policies and proposals of our party and of myself as well, and then fails to acknowledge the mistakes and the errors in his own record. It's just astonishing to listen to him," Romney said on the Sean Hannity radio show.
"There's no question that under this president, this recovery has been the most tepid, the most weak, the most painful since the beginning of our recorded economic history."
Romney has met stubborn skepticism from conservatives, who fear that the former governor of liberal Massachusetts will tack to the left once he wins the nomination in order to appeal to independents.
That scenario is fodder for Santorum, a harsh critic of abortion and gay rights who has tapped into conservative angst about the frontrunner.
But exit poll data from Maryland suggests Romney may be turning a corner with lower-income Americans and the most conservative of voters, people Santorum has counted on throughout the campaign.
Wisconsin was the contest seen as the most critical of the night by many Republicans.
"Ultimately, the winner out of this (Wisconsin) contest... is going to have some serious bragging rights," Republican National Committee chairman Reince Priebus told CNN.
But he wouldn't be drawn on whether it could spell the end for Santorum, a former senator, or Gingrich, who is trailing far behind.
"We'll see the fallout of tonight tomorrow," Priebus said.
Romney has now won 24 out of 37 contests and amassed some 630 delegates of the 1,144 needed, according to CNN's tally.
Santorum has racked up 11 victories and has well under half Romney's delegate count.
