And former House speaker Newt Gingrich was only a few points ahead of libertarian congressman Ron Paul in a battle for second place, CNN and Fox television channels said.
Official figures by the Nevada Republican Party, with 12.5 percent of votes counted, gave Romney 40.8 percent, against 26.2 percent for Gingrich, 19.2 percent for Paul and 13.6 percent for Santorum.
Gingrich, who scored an upset win by taking South Carolina last month, is struggling to stay in the race in face of Romney's superior funds and well-oiled campaign machine.
He was due to address the media later Saturday, but his daughters insisted he plans to stay in the race, with all eyes already on March 6, Super Tuesday, when at least 10 states will vote for their Republican nominee in the November elections.
"He's in it to win it. We're working towards a victory or towards being in Tampa in August. So this is a long and fluid race. But... we are here for the long haul," his daughter Kathy Lubbers told CNN, referring to the party convention in August which will crown the nominee.
But David Damore, assistant professor of politics at the University of Nevada, Las Vegas, said it was a blow to Gingrich.
"I think that super Tuesday is his last stand. The party is still fractured... It does look like Paul is costing Gingrich a bit and that will probably be the case in the caucus states," he told AFP after the initial results came in.
The Silver State was voting four days after Romney's crushing win over the former House speaker in Florida.
If Paul creeps into second place in Nevada it will be the best showing yet for the politician who has long set his sights on the White House, but has found it hard to sell his unconventional message and radical economic views, including his opposition to the Federal Reserve.
But his populist message plays well in caucuses, and Paul vowed he was not planning to drop out before Super Tuesday.
"We are doing so well there is no reason to think about that. We are starting to see the accumulation of delegates," Paul told CNN.
"After tonight we'll have more. And next Tuesday we'll have more. And I think other people will be starting to think about our position and we may well by that time be in second place."
Three states will vote on Tuesday -- Colorado, Minnesota and Missouri -- and Romney is hoping a Nevada win will help him sweep into the heartland states where unemployment and the struggling economy are top issues.
Romney had been expected to repeat his triumph here of the 2008 White House race when he won the state over John McCain -- helped by strong backing from fellow Mormons.
"Everybody knows he's going to win, it's about how big he wins, and how much of the vote he gets," said Damore. "They're basically competing against expectations now: can he do better than 50 percent, which is about what he got four years ago?"
Nevada will be Romney's third victory over Gingrich, after scoring wins in New Hampshire and Florida, and he seems to have tamped down a row that broke out after he said he was "not concerned" about "very poor" Americans.
He insisted the context of his comments showed he was concerned about all Americans, but his focus is on middle class voters who have been worst hit by a recession and sluggish US recovery after the 2008 global downturn.
The remarks about the poor sparked new accusations that the wealthy former venture capitalist, who lives off his investments, is out of touch with ordinary voters.
Romney also raised eyebrows after he released tax filings showing he earned $20 million from his investments in 2010 and paid just 13.9 percent in taxes -- a lower rate than many struggling Americans.
But voting in Las Vegas Saturday, 73-year-old Carl Lindstrom said the former Massachusetts governor would also get his vote. "I think he has the presence, the prestige, the knowledge," he said.