Second-half goals from Eddie Johnson and Landon Donovan were enough to give the USA a win which puts them on 16 points and top of the CONCACAF World Cup qualifying group, a point clear of Costa Rica.
If Honduras win or draw against Panama, Jurgen Klinsmann's side will be guaranteed a place at Brazil 2014.
Mexico, under coach Luis Fernando Tena for the first time, are in danger of missing out on a berth but should still get a play-off place despite their poor campaign.
For the USA, they maintained their fine record at home in World Cup qualifiers, unbeaten since 2001 thanks to the win at Columbus Crew Stadium.
The visitors were the better side early on, creating space out wide which almost led to a seventh-minute opener.
DaMarcus Beasley miscued his attempted clearance of a cross but fortunately for him it fell straight into Tim Howard's arms.
There were a flurry of chances midway through the first half, starting with Mexico's opportunity in the 19th minute.
USA defender Omar Gonzalez crucially broke up play but the chance developed for Christian Gimenez, whose shot was just too narrow and palmed away by Howard.
Gimenez curled a free-kick just over from a tough position out wide before Clint Dempsey had a shot deflected into the arms of Jose de Jesus Corona after a delightful flick by Johnson.
Villarreal attacker Giovani dos Santos was unsuccessful in trying to win his side a penalty on 24 minutes when he went down easily in the area.
The chances kept coming as Jermaine Jones' 25-yard effort went just wide and Donovan took one touch too many before his shot was blocked in the area.
Klinsmann's men should have gone ahead on 32 minutes through Johnson.
Donovan's corner was perfectly placed and the Seattle Sounders forward, unmarked and rising uncontested, should have done better with his header but Corona held onto the save down low.
Mexico created an excellent chance of their own just before half-time through Dos Santos.
With the USA defence deciding to backpedal, Dos Santos had time and space on the edge of the area but his strike lacked power and direction and Howard made a good save.
Howard kept out Diego Reyes' header on the stroke of half-time as both teams went into the break without a goal despite their chances.
The hosts found the opener in the 49th minute thanks to Johnson and in similar fashion to the chance he failed to take in the first half.
Donovan's corner was again in a dangerous area and Johnson headed into an open goal after Corona came out and was caught in no man's land.
After an uneventful second half, the USA sealed the points in the 78th minute when Donovan tapped in at the back post after a Mikkel Diskerud cross.
It came after poor defending from Mexico, with a poor clearance particularly costly before Diskerud found space to set up the sealer and all but guarantee the USA a seventh straight World Cup appearance.
Dempsey won a penalty for the US in the dying moments but he blazed it wide and high.
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