President Barack Obama went hard after Romney, assuming the GOP nomination fight was no longer in doubt.
There were 95 delegates at stake for the day, including 42 in Wisconsin, the only one of the three contests that Santorum seriously contested.
Even before the votes were counted, Romney was campaigning like the nominee-in-waiting, focusing on Obama and amassing endorsements from prominent officials inside the party he will lead into the general election campaign.
Romney had 572 Republican National Convention delegates, exactly half of the 1,144 needed to win the nomination, on a pace to clinch by the end of the primary season in June. Santorum had 272, Newt Gingrich had 135 and Ron Paul had 51.
Though the national economy has been improving, polls show voters are concerned about the rising cost of gasoline, and Romney is seeking to take advantage of that.
He said of Obama on Tuesday, "He gets full credit or blame for what's happened in this economy, and what's happened to gasoline prices under his watch and what's happened to our schools and what's happened to our military forces." Romney spoke to supporters in Waukesha, Wis.
Earlier, in an interview with Fox News, he said it was important for his party "to get a nominee as soon as we can and be able to focus on Barack Obama." He blamed President George H. W. Bush's 1992 loss to Bill Clinton on Ross Perot, who ran as an independent and presumably took Republican votes from Bush in the general election.
Obama, in Washington, was in full campaign mode, too, accusing the Republicans of trying to force a "radical vision" on the nation with proposals that would help the rich at the expense of the middle class, senior citizens, students and the poor.
He said the GOP was so out of control that Ronald Reagan "could not get through a Republican primary today."
Wisconsin was the fourth industrial state to vote in a little more than a month after Michigan, Ohio and Illinois, a string that Romney has exploited to gain momentum as well as a growing delegate lead in the campaign for the Republican presidential nomination.
The former Massachusetts governor won a close Michigan primary on Feb. 28, then an even closer one in Ohio a week later, followed by a convincing victory in Illinois on March 20. At each turn, he was backed by his own robust, well-financed organization as well as a deep-pocketed super PAC that assured him of an overwhelming advantage in television advertising.
In Wisconsin, Romney and the super PAC, Restore Our Future, spent roughly $3 million on television ads compared to about $850,000 for Santorum and the Red, White and Blue Fund, a super Pac that supports the former Pennsylvania senator. Much of the Romney-aligned super Pac advertising consisted of attacks on Santorum.
As was the case in Michigan and Ohio, private polling showed Romney trailing in Wisconsin a few weeks before the vote. But he overtook his rival in public surveys as the televised attacks took their toll.
Already, the early outlines of a general election ad war are visible. Obama's re-election campaign is airing commercials in a half-dozen battleground states that accuse Romney of siding with Big Oil "for their tax breaks, attacking higher mileage standards and renewables."
The ads are a rapid response to $3 million in commercials aired by an outside group, American Energy Reliance, blaming the president for rising gasoline prices.
In his campaign for the Republican nomination, Romney has collected endorsements from former President George H.W. Bush, Florida Sen. Marco Rubio, a tea party favorite, and Rep. Paul Ryan of Wisconsin, author of a conservative budget that Republicans pushed through the House last week and is certain to play a prominent role in the fall campaign for the White House.
At the same time, Romney continues to struggle for support from some of the party's most reliable conservative voters. In the past five weeks, while winning across the Midwest, he has lost to Santorum in Alabama, Mississippi and Louisiana, all part of the traditional Southern political base.
Santorum made little or no effort in Maryland, was not on the ballot in Washington, D.C., and concentrated much of his time in Wisconsin in rural areas. He all but conceded defeat in advance in Wisconsin, retreating to Mars, Pa., for an election night appearance in his home state.
Pennsylvania is one of five Northeastern states with primaries on April 24, the next date on the Republican calendar after a three-week intermission.
Santorum has conceded he's not going to amass the delegates needed to win the nomination by the time convention opens, but his strategy - and hope - is to prevent Romney from doing so. Campaigning in Appleton, Wis., on Monday, he said a struggle at the convention over the nomination would be a "fascinating display of open democracy" and would encourage more Republican voters to participate in the election.
Romney wants no part of an open convention, and increasingly, senior party leaders agree and are willing to say so.
With all the endorsements Romney has received in recent days, a non-endorsement from Senate Republican Leader Mitch McConnell got attention, too.
"It seems to me we're in the final phases of wrapping up this nomination," he said over the weekend, adding that most members of the party in the Senate "are either supporting him or they have the view that I do, that it's time to turn our attention to the fall campaign and begin to make the case against the president of the United States."
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David Espo reported from Washington.
