Goals from Jordan Morris and Juan Agudelo in the second half saw the US to their victory at the Alamodome.
Jurgen Klinsmann's team were mostly the better side throughout in San Antonio, and they were rewarded after the break.
Both teams were below full strength and it showed for large parts, with neither particularly able to get going.
The US were bright early on without creating any clear-cut chances.
Both teams tried their luck from range - without seriously threatening - and often broke down in the middle and attacking thirds.
Mexico went close to opening the scoring five minutes before half-time.
The overlapping Gerardo Flores beat his man before crossing to the near post, but Eduardo Herrera hit the side-netting with the difficult chance.
In his first senior international start, Morris gave the US the lead in the 49th minute and it was a fittingly scrappy goal.
The 20-year-old, who has never played a professional game, got on the end of a loose ball and used his speed before finishing cooly past Cirilo Saucedo.
Agudelo doubled the lead in the 72nd minute with a tremendous goal.
The New England Revolution forward brought down a Michael Bradley pass with a superb first touch before cutting inside and firing past Saucedo, who could have done better.
Bradley almost sealed the win in the 79th minute, but his in-swinging corner was cleared off the line.
Yet it did not matter as Mexico rarely threatened as the US enjoyed a win over their archrivals.
