As the region's top seed, the US were given a bye into the third round and showed their class by opening a 2-0 lead against their Caribbean opponents, then added a third goal late on to spare any blushes after Antigua had pulled one back.
Defender and captain Carlos Bocanegra gave the home team a perfect start when he scored in the eighth minute after Antigua goalkeeper Molvin James parried a corner straight to him.
The Americans doubled their lead just before halftime when Antigua defender Martin McCoy brought down Landon Donovan in the penalty area and Clint Dempsey converted the spot kick.
The US lost Jose Torres, who was moved from his usual position at midfield to left back, early in the second half when he was stretchered off, forcing a reshuffle at the back that led to a goal for the visitors.
Antigua, with a population just a little more than the capacity of the 75,000-seat Raymond James Stadium in Tampa, briefly raised the prospect of an upset when Peter Byers scored two minutes after he came on midway through the second half.
"It was a tricky game. They were difficult to break down," US manager Juergen Klinsmann said.
"Antigua and Barbuda did a good job of defending. They made if difficult for us to create chances."
"This was a reality check. We are going to wear everyone down but we need to play faster out of the back."
Antigua presented the Americans with some awkward moments but recalled striker Herculez Gomez restored his team's two-goal advantage when he hammered home from point-blank range five minutes later.
"They should feel proud," Antigua coach Tom Curtis said about his players. "They are disappointed they didn't get closer.
"I'm proud of the players. We competed really well and gave them a scare."
The US and Antigua are among 12 teams competing in the third round of CONCACAF qualifying. The top two from the three groups of four advance to a final single pool round with the leading three booking automatic berths for the Brazil finals.
In the group's other game, Jamaica opened their campaign with a 2-1 home victory over Guatemala.
The next match for the US is away to Guatemala on Tuesday, while Antigua are at home to Jamaica.