Romney, the former Massachusetts governor, consolidated his front-runner status with a string of victories in the 10-state Super Tuesday vote, even as Santorum held his own in key southern states.
Santorum kept his hopes alive with a trio of victories in North Dakota, Oklahoma and Tennessee, but Romney took six states: Idaho, Massachusetts, Virginia, Vermont, Alaska and the most closely watched contest, Ohio.
In a further twist, former House speaker Newt Gingrich also won one, his home state of Georgia. With no clear winner, the battle is still on to be the nominee to challenge Democrat President Barack Obama in November polls.
"I think the long slog continues for Mitt Romney towards the nomination," Dante Scala, a professor of politics at the University of New Hampshire, told AFP with the candidates now eyeing upcoming votes in March and into April.
Still, Super Tuesday left little doubt in analysts' minds that Romney will eventually secure the crown as Republicans bid to deny Obama a second term.
And despite being battered, millionaire businessman Romney, 64, can boast that he is a survivor, despite lingering skepticism among his party of his conservative credentials.
He has now won primaries in both Florida and Ohio, two swing states Republicans must win to claim the White House.
Romney ended up taking Ohio by more than 10,000 votes, or one percent of the vote, denying Santorum his central argument that he alone can compete against Obama in working-class, Midwestern swing states.
"We're on our way," Romney told supporters in a ballroom in the Westin Hotel in Boston. "I'm not going to let you down. I'm going to get this nomination."
House Majority leader Eric Cantor, who on Sunday became the first of the top Republican leadership to endorse Romney, said he believed the former governor was inexorably heading towards the nomination.
"Romney did what he needs to do," Cantor told Fox television.
"What we're beginning to see is people saying that jobs and the economy undoubtedly are the number one issue and we need Mitt Romney because he's the only individual in the race who has a plan, a pro-growth bold plan to get the economy back on track and get jobs created again."
All four remaining candidates -- including Texas congressman Ron Paul who failed to win a single state on Tuesday -- are focused on the all-important hunt for the 1,144 delegates needed to win the nomination.
In the complex Republican race, each state is allocated a certain number of delegates to the party's summer convention which will crown the nominee, and those delegates are divided up among the winners of the state votes.
According to the authoritative website Real Clear Politics, Romney was about third of the way towards the nomination, leading the delegate count Wednesday with 404, Santorum had 161, Gingrich 105 and Paul trailed last with 61.
Santorum, 53, a devout Roman Catholic who fiercely opposes abortion and gay marriage, has billed himself as the only authentic conservative in the race who understands working-class voters and can beat Obama in the fall.
"We have won in the West, the Midwest and the South and we're ready to win across this country," he told an ear-splitting rally Tuesday.
But Santorum's radical views have alienated some moderates, and after the Ohio setback serious questions will be asked about his electability as the race heads to Kansas and some of the US territories on Saturday.
Santorum was back on the campaign trail stumping in Kansas on Wednesday, before two rallies in Mississippi later in the day.
Romney has now won 14 states, while Santorum has won seven and Gingrich two. But the next states in play could rob Romney of any forward movement.
Deeply-conservative Kansas votes on Saturday and the delegate-rich southern states of Alabama and Mississippi hold primaries Tuesday, all of which could prove a challenge to Romney, and hand victories to either Santorum or Gingrich.
"We'll go day by day, step by step, door by door, heart to heart. There will be good days, there will be bad days," Romney vowed to supporters Tuesday.
"But on November 6th, we're going to stand united. Not only having won an election, but having saved a future."