About a half-hour after the polls closed at 8 p.m. Eastern time, 6 percent of precincts had reported ballot totals and Romney led his main rival by nearly double the number of votes.
Exit polls showed voters siding with Romney on key issues like electability and empathy. ABC News projected Romney would win.
Romney has won more states and more delegates than has any other candidate in the GOP primary, but he has struggled to sustain a narrative of an undisputed front-runner.
All of Romney's opponents have questioned his strength because of his apparent weakness with the conservative voters who have voted in the primary so far, and they have vowed to stay in the contest until the party's summer convention.
Even Romney's win in Illinois tonight cost him. He and the super PAC supporting him outspent Santorum's forces by an eight-to-one margin on campaign advertising.
Romney is set to win most of the 69 delegates at stake in Illinois. Santorum didn't even qualify for the ballot in four of the 18 congressional districts in the state, making him ineligible for 10 of those delegates.
After Santorum won a string of primaries in southern states by winning over social conservatives and religious voters, Romney's campaign has shifted its storyline to argue that the former Massachusetts governor is the only candidate who can mathematically win the nomination by getting 1,144 delegates.
The other candidates, meanwhile, continue to insist that they are the only ones who can beat President Obama in a general election.
Exit polls from Illinois found that six in 10 voters, who were typically less ideological than Republicans in the states Romney has lost, said Romney had the best chance of beating Obama. The front-runner also led Santorum narrowly as the candidate who voters said understands their problems the best.
Romney badly needed to win big in Illinois to deny Santorum the momentum he has gained as he added southern states to his win column, most recently Alabama and Mississippi a week ago.
Gallup reported as Illinoisans voted that Romney's lead over Santorum nationally was 34 percent to 30 percent, though the former Pennsylvania senator is still the preferred choice among conservatives and Midwestern voters. That national measure has also swung back and forth like a heavy pendulum; in the middle of February, for example, Santorum led Romney by 10 points.