A Rafael Marquez header in the 89th minute changed all that.
For the first time since 2001, a streak stretching back 30 games unbeaten, the USMNT lost a home qualifier and put an end to a stretch of qualifying wins known as Dos A Cero.
Miguel Layun got Mexico on the board midway though the first half when he capitalized on a lose ball in the American's half. Michael Bradley won a 50/50 challenge and was trying to take possession of the ball but it was Layun who reacted first and hit a speculative shot that deflected off John Brooks and past a screened Tim Howard.
Things went from bad to worse for the USA as keeper Howard picked up a groin injury right before halftime and had to be substituted out for Brad Guzan. Howard made a fingertip save early in the match that put a Javier Hernandez shot onto the post. Carlos Vela also hit the woodwork in the first half as Mexico pressed well against a disorganized US formation.
Eventually the US settled into a more familiar four-man backline and found their stride in the match and the American's found their goal early in the second half. Jozy Altidore used some solid hold up play and then found a streaking Bobby Wood who slotted home through traffic as Alfredo Talavera saw the ball go off one of his defenders and his arm before settling in the back of the net.
The remainder of the half grew increasingly chippy as Guatemalan referee Walter Lopez settled numerous dust ups and issued a total of nine yellow cards, including six in the second half.
But for all their hard work and forcing Talavera into several fine saves, it was Mexico who would take advantage of a late corner. Layun would find Marquez unmarked at the near post in the 89th minute on a corner kick and a simple flick header up and over Guzan into the back post gave Mexico a decisive win in CONCACAF qualifying.
Mexico will be without Carlos Salcedo however, who picked up a second yellow card for time wasting in stoppage time though Mexico saw out the final seconds with 10 men with no issues. Also, Salcedo entered the match as a first half substitute for Andres Guardado who picked up an injury of his own.
The USA will now head to Costa Rica on Tuesday and face the daunting task of getting a positive result against Los Ticos, something the USMNT has never done in World Cup qualifying. It's still very early in the qualifying round but the US is already in a very large hole.