But Central America's Honduras and Panama are hoping to produce upsets and end the run of two straight finals between the big two North American teams.
Mexico, who have been in electrifying form in the tournament, face the tougher test, on paper at least, when they take on Honduras - the top ranked team from Central America.
The U.S. have a chance to avenge their 2-1 group stage loss to Panama which was the biggest upset of what has been, so far, an exciting tournament.
CONCACAF structures the draw for the 12-nation tournament to almost ensure that Mexico and the U.S. do not meet before the final - the pair have won nine of the ten Gold Cups and guarantee the biggest television audience.
Mexico have been playing with flair and confidence allied to the prolific goalscoring of Manchester United striker Javier Hernandez, who is the tournament's top scorer with six goals from four games, including an audacious back-heeled winner in the 2-1 quarter-final victory over Guatemala.
Given the large immigrant community, the majority of Wednesday's crowd at the home of NFL team the Houston Texans will be chanting the name of Hernandez, known as 'Chicharito' to the Mexican faithful.
MEXICO FAVOURITES
The performances of El Tri have certainly not gone unnoticed by U.S. midfielder Landon Donovan who says the Mexicans have lived up to their pre-tournament billing as favourites.
"Mexico are playing fantastically at the moment, they have looked like the favourites in all their games and when you have a player like Chicharito, well, everything's possible," Donovan told reporters on Tuesday.
Mexico have benefitted from a ruling this week that allowed them to replace five players who had tested positive for banned substance clenbuterol in controls taken before the tournament.
While relieved to have a full squad to choose from again, Mexico coach Jose Manuel de la Torre will know that Honduras, who qualified for last year's World Cup finals in South Africa, will offer a stern test.
Striker Jerry Bengtson was on target in the quarter-final win over Costa Rica, which Honduras won on penalties after extra time and the 24-year-old has emerged as a real danger-man for Los Catrachos.
The task for Donovan and company is to avoid tripping up for the second time against a Panama team who, while missing suspended striker Blas Perez, showed they have the character, physique and skill to beat the U.S.
The 2-1 victory in Tampa was the first success against the United States for the 'Canal men' and was a real wake-up call to a U.S. team who had looked flat up to that point.
"It's nice to get a chance to play again so quickly against a team we lost to," said skipper Carlos Bocanegra.
"We gave up two soft goals, two defensive lapses... we need to bit a little sharper defensively but we are still really confident," he added.
Panama's win on penalties over El Salvador on Sunday came at a price with Perez sent off in t
