The US begin their campaign in Florida against a team who reached the current stage by winning a second-round group containing Haiti, Curacao and the US Virgin Islands. Antigua and Barbuda are arguably the weakest team left in the CONCACAF qualifying competition, while the US are expected to book their place at Brazil 2014.
Coached by former Germany striker Klinsmann, the Americans had two disappointing performances in their last friendlies, losing 4-1 to Brazil's Olympic team and being held 0-0 by Canada.
But Howard knows it should be a different outcome this time, with Antigua and Barbuda competing at this stage for the first time and made up largely of the players from Antigua Barracuda FC - a club side who play in the third division of the US league.
"We're at home so we need to win," Everton keeper Howard said. "We need to really put a lot of pressure on them and make them feel like they're going to be in a really difficult game."
Alongside the US in Group A are Jamaica, who last qualified for the FIFA World Cup in 1998 and begin their campaign against Guatemala tomorrow.