A 10-day break follows before Washington, D.C., Maryland and Wisconsin hold primaries on April 3.
Santorum is not on the ballot in the nation's capital.
Private polling shows Romney with an advantage in Maryland, and Restore Our Future launched a television ad campaign in the state during the day at a cost of more than $450,000.
Wisconsin shapes up as the next big test between Romney and Santorum, an industrial state next door to Illinois, but one where Republican politics have been roiled recently by a controversy involving a recall battle against the governor and some GOP state senators who supported legislation that was bitterly opposed by labor unions.
Already, Restore Our future has put down more than $2 million in television advertising across Wisconsin. Santorum has spent about $50,000 to answer.
Neither Newt Gingrich nor Ron Paul campaigned extensively in Illinois.
Gingrich has faded into near-irrelevance in the race, but he was defiant in a statement issued after Romney sealed his victory.
"To defeat Barack Obama, Republicans can't nominate a candidate who relies on outspending his opponents 7-1. Instead, we need a nominee who offers powerful solutions that hold the president accountable for his failures," it said.
Gingrich said his campaign will spend the time leading to the party convention "relentlessly taking the fight to President Obama."
Illinois fell into Romney's column far more easily than Michigan or Ohio had.
The night's vote count was plagued by ballot difficulties. Rupert Borgsmiller, executive director, of the Illinois State Board of Elections, said in late afternoon that 25 counties and the city of Aurora were affected by the ballot problem. He didn't know how many ballots were affected but said "clearly you can say more than hundreds."
Romney and Santorum campaigned energetically across the state, and not always in respectful tones.
"Senator Santorum has the same economic lightweight background the president has," Romney said at one point. "We're not going to replace an economic lightweight with another economic lightweight."
Santorum had a tart reply. "If Mitt Romney's an economic heavyweight, we're in trouble."
Anticipating a primary defeat, Santorum's campaign argued that the race for delegates is closer than it appears.
Santorum contends the Republican National Committee at the convention will force Florida and Arizona to allocate their delegates on a proportional basis instead of winner-take-all as the state GOP decided. Romney won both states.
On Tuesday, about four in 10 voters interviewed as they left their polling places said they were evangelical or born again. That's about half the percentage in last week's primary states of Alabama and Mississippi, where Santorum won narrowly. Despite an unusually lengthy race for the nomination, less than a third of those voting said in the polling-place survey they hoped the primary season would come to a quick end even if that meant their candidate might lose the nomination.
The findings came from preliminary results from the survey of 1,555 Illinois Republican voters, and had a margin of error of plus or minus 4 percentage points. The exit poll was conducted for The Associated Press and the television networks by Edison Research at 35 randomly selected polling places around the state.
As Illinois Republicans voted on Tuesday, Romney raised more than $1.3 million at a luncheon in Chicago.
Illinois was the 28th state to hold a primary or caucus in the selection of delegates to the nominating convention, about halfway through the calendar of a Republican campaign that has remained competitive longer than most.
A change in party rules to reduce the number of winner-take-all primaries has accounted for the duration of the race. But so has Romney's difficulty in securing the support of the most conservative of the GOP political base. Santorum and Gingrich have struggled to emerge as the front-runner's sole challenger from the right.
David Espo reported from Washington
- Wyoming ranked third in US in percentage of...
- Test anxiety: How cold feet are ruining your...
- Hometown pastor says community stands by...
- Sen. Harry Reid's retirement recalls his...
- 'A marvellous work and a wonder': A look back...
- Drownings along Rio Grande spike after...
- O'Malley: Presidency 'not some crown'...
- Hundreds rally against Indiana law, say it's...
- Student loan recipients on 'strike'... 83
- Rep. Trey Gowdy: Hillary Clinton wiped... 49
- Sen. Harry Reid's retirement recalls... 40
- Indiana lawmakers try to quiet... 37
- Senate's Harry Reid announces he won't... 34
- Hundreds rally against Indiana law, say... 26
- Delete, erase, shred: The enemies of... 15
- O'Malley: Presidency 'not some crown'... 13