Returns from 98 per cent of Illinois' precincts showed Romney gaining 47 per cent of the vote compared to 35 per cent for Santorum, nine per cent for Ron Paul and eight per cent for a fading Newt Gingrich.
"What a night," Romney said in his victory speech before he directed his remarks at U.S. President Barack Obama.
"It's time to say this word: 'Enough.' We know our future's brighter than these troubled times. We still believe in America and we deserve a president who believes in us, and I believe in the American people."
Santorum, meantime, took to the stage in his home state of Pennsylvania, in the Civil War town of Gettysburg.
"I think this is the most important election since the election of 1860," Santorum said of Abraham Lincoln's electoral triumph 152 years ago.
"What's at stake in this election is freedom."
Santorum had been hoping for a game-changing upset in Illinois, another so-called Rust Belt state he was hoping would be receptive to his working-class roots. Fifty-four delegates were at stake in the state.
The former Pennsylvania senator believed victory in Illinois might have put him within striking distance of Romney in terms of delegates amassed in a presidential race that has proven wildly unpredictable.
Santorum, after all, rode into Illinois on a wave of momentum following primary victories last week in Alabama and Mississippi, but that momentum proved as fleeting as it has throughout the race for every winning candidate.
Santorum fumbled by spurning Illinois last week to campaign in Puerto Rico, where he was photographed sun-bathing and offended primary voters by saying the island must adopt English as its official language if it hopes to become a state.
Romney went on to win the Puerto Rico primary with more than 80 per cent of the vote.
Nonetheless, the Louisiana primary is being held on Saturday — a contest in yet another Deep South state that could give Santorum another win and yet another jolt of momentary momentum. Even so, the mathematics are increasingly working against him as Romney continues to rack up delegates.
Romney, as always, vastly outspent his rivals in Illinois.
Television ads against Santorum proved damaging to his campaign, and he didn't help himself on Monday when he said he didn't care about the unemployment rate.
"We need a candidate who's going to be a fighter for freedom; who's going to get up and make that the central theme in this race because it is the central theme in this race," Santorum said on the campaign trail in the so-called Prairie State.
"I don't care what the unemployment rate's going to be. Doesn't matter to me. My campaign doesn't hinge on unemployment rates and growth rates. It's something more foundational that's going on."
Santorum later tried to back away from the remark.
"Of course I care about the unemployment rate, I want the unemployment rate to go down, but I'm saying my candidacy doesn't hinge on whether the unemployment rate goes up and down. Our candidacy's about something that transcends that. It's about freedom."
As primary day dawned in Illinois, polls had Romney well ahead of Santorum, with a Public Policy Polling survey putting him a whopping 15 points ahead of Santorum.
That was despite Santorum's strong showing in the state as recently as a week ago.
The upstart candidate even urged his supporters in Illinois, the most populous state in the race so far after Florida, to help him stage an upset that would "shake up this race like no state can shake it up."
But Romney's so-called Super PAC spent almost US$4 million discrediting Santorum, largely in the Chicago area, about his record when he served as a senator for Pennsylvania in U.S. Congress before losing in a landslide to his Democratic opponent in 2006.
One ad asked: "If his own state didn't trust Santorum, why should Illinois?"
Romney's prospects in Illinois were also enhanced by the fact that Santorum failed to qualify for 10 of the state's 54 delegates.
Romney has 563 delegates in the overall count maintained by The Associated Press, out of 1,144 needed to win the nomination. Santorum has 263 delegates, Gingrich 135 and Paul 50.
Although he appears to be trudging slowly but steadily to victory, Romney's failure to unite and excite the Republican base has been troubling to many within the Republican party. Even one of his boosters, Arizona Sen. John McCain, acknowledged his onetime presidential rival's difficult path to victory.
"I think he has not done as well as we'd hoped — none of us ever do in campaigns," McCain told Fox Business Radio on Tuesday.
"I think he's a very fine and decent person, I think he's got a fine family, I think he has all the right principles .... He has run a good campaign, and I think he will be the nominee."