After a rough start to the first half, the United States battled back to equalize against Mexico and had the run of play for most of the second half.
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.