But even in victory Mr Romney seemed to confirm some of the fears about his viability as a general election candidate. He stumbled repeatedly in his speech, at one point saying he looked ahead to an America that was "humbled", before correcting himself to say "humble".
Even Mr Romney’s own supporters, including the 2008 nominee John McCain, have said publicly that their relatively moderate candidate needs to “do better” and lacks the spark needed to enthuse voters.
Despite his defeat, Mr Santorum promised to stay in the race in the belief that he can play the spoiler and stop Mr Romney from reaching the “magic number” of 1,144 that would win him the nomination outright. Mr Romney now has 563 delegates. Mr Santorum has 263, Mr Gingrich 135 and Mr Paul 50.
Speaking near Gettysburg, Pennsylvania - the site of the bloodiest battle of the American Civil War - Mr Santorum said the US faced its most important election since 1860, when it elected Abraham Lincoln on the eve of civil war.
Facing charges of being an "economic lightweight", Mr Santorum attempted a last-ditch appeal to conservatives unimpressed with Mr Romney's economy-focused message.
"The foundational issue in this race, one that is in fact the cause of the other maladies that we're feeling - whether it's in the economy or the budget crisis - boils down to one word: freedom," he said.
Newt Gingrich looked set to come a humiliating last place, falling behind Ron Paul, the libertarian congressman who has openly said he has little chance of winning the nomination.
The loss leaves Mr Santorum fighting once again to maintain the credibility of a campaign which has been drained of momentum in recent days by a series of gaffes and organisational failures.
A day before yesterday’s vote Mr Santorum, who relies on support from the Republican party’s evangelical base, had talked of a scoring a “huge or surprise win” that would have “guaranteed” him the nomination.
But in a damaging 48 hours ahead of the Illinois primary, Mr Santorum found himself on the defensive after letting slip that he “didn’t care” about the unemployment rate.
“I don't care what the unemployment rate's going to be,” he said at an Illinois campaign event, “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.”
The clumsy remarks - which were intended to appeal to conservatives concerned about social issues and religious freedom - were seized upon by Mr Romney.
“One of the people who is also running for the Republican nomination said that he doesn't care about the unemployment rate; that does bother me,” Mr Romney said gleefully, “I do care about the unemployment rate. It does bother me. I want to get people back to work.”
Later, Mr Santorum said of remarks that he wished he “had a do-over”, but political analysts say that such amateurishness and indiscipline, which has always plagued the shoestring Santorum campaign, is starting to tell.
Strategists also say Mr Santorum made a serious mistake wasting two days of the Illinois race by campaigning in Puerto Rico last week.
He was also unable to win delegates in four of Illinois’s 19 congressional districts after his campaign failed to register before electoral deadlines expired.
Mr Santorum’s fiery brand of Catholicism has proved a double-edged sword, stirring support among rural voters and religious evangelicals but deterring more moderate urban voters, including fellow Catholics who have repeatedly backed Mr Romney.
Mr Santorum was forced to defend his ultra-conservative views after video footage surfaced showing him applauding a Baptist pastor at a church service in Louisiana last Sunday after the minister delivered a rant against gay people, liberals and women who have abortions.