Romney also won primaries in Maryland and Washington D.C.
A total of 98 delegates was at stake Tuesday night.
Romney hopes the win in Wisconsin will add to the aura of inevitability surrounding his campaign. He has now crossed the half-way point in gathering the delegates needed to win the nomination.
In Milwaukee, the candidate accused of being out of touch tried to stick that label on Barack Obama.
"It's enough to make you think that years of flying around on Air Force One, surrounded by an adoring staff of true believers telling you what a great job you are doing, well, that might be enough to make you a little out of touch," Romney said.
Despite a trio of losses Tuesday night, Rick Santorum showed no signs of giving up.
"We won't win by moving to the middle, we win by moving to the middle," he said. "We win by getting people in the middle to move us and move this country forward."
Santorum called Tuesday's primaries the kick-off to the second half. The next primary is three weeks away and includes his home state of Pennsylvania.
His local supporters insist Santorum isn't playing the role of spoiler.
"If you remember back to 2008, up to June 5, there was a battle royale between Barack Obama and Hillary Clinton, it certainly didn't make them weak and I don't think it makes us weak," said Steven Polit, Santorum Illinois alternate delegate.
A new poll shows the hurdles Romney may face. The president has his largest lead yet nationally. In 12 key swing states, Obama leads Romney 51 to 42 percent.
"It's going to be a fight," said Selena Pacheco, a voter from Kenosha, Wisconsin. "Hopefully the other two candidates will drop out because I don't think they've done very well."
Exit polling indicates 8 in 10 Wisconsin voters think Mitt Romney will be the Republican nominee. Those same polls showed those who cast a ballot Tuesday said they were more interested in a candidate's ability to beat Barack Obama than with the strength of his conservatism or stand on the issues.Santorum would have to win 79 percent of the remaining delegates to clinch the nomination.