The 54-year-old Romero shot a final round 3-over 73 but was never seriously challenged by Fred Funk (75), who finished four strokes back.
Romero was 6-under 274 for the tournament.
Funk, who began the day two shots back, predicted Saturday that hed have to make his move on the front nine and then just hold on.
He did neither, failing to cut into the deficit and then watching his quest to become the fifth straight come-from-behind winner die with a triple-bogey on the par-4 13th.
Mark McNulty (68) finished in third, five shots back. Greg Norman shot a 70 and finished in fourth, his third straight top-5 finish.
But Norman, the 53-year-old Australian who held the 54-hole lead at the British Open two weeks ago, is skipping the PGA Championship at Oakland Hills next week. His honeymoon with tennis great Chris Evert over, he said he needs to return to work as CEO of Great White Shark Enterprises.
Romero, one of the big hitters on the Champions Tour, is the first international winner at the U.S. Senior Open since Australias Graham Marsh in 1997 and the first to hold both the 54-hole lead and the trophy since Bruce Lietzke in 2003.
Although several deer and fawn showed up Sunday on the cragged course carved out of the Rocky Mountain foothills, there werent any more sightings of black bears like the one that interrupted the tournament Friday.
Volunteers did arrive at dawn to discover a bear had visited the concession stand at the seventh hole overnight and helped itself to a smorgasbord of candy bars, bananas, hot dogs and bread.
And a foe and two fawns crossed the 14th fairway Sunday, where Norman hit a long drive over them and Juan Quiros had to wait as the deer trotted off into the trees.
Other than that, the only interruption of the final round was a 23-minute weather delay when the leaders were on the fairway on the sixth hole.
Romero can expect a heros welcome when he returns to Villa Allende in central province of Cordoba, the same city where his Argentine compatriots held a parade for 2007 U.S. Open champion Angel Cabrera, whom Romero once sponsored on the European Tour.
Romero said both Cabrera and De Vicenzo, the godfather of golf in Argentina, called him this week to offer encouragement. He said De Vicenzo told him, I think this is your week.
He was right.
Romero grabbed the lead on the 12th hole Saturday, led by two strokes heading into the final round and never gave the rest of the field a chance to catch him on Sunday.