Michael Orozco Fiscal's 79th-minute goal gave the United States a first ever away win over Mexico.
Mexico entered the contest at Mexico City's Aztec Stadium with a formidable home record against their neighbours.
The United States had lost 23 matches and drawn just one against El Tri in 75 years of matches in Mexico.
However, Orozco Fiscal's first international goal, a left foot finish from close range in the 79th minute, gave Jurgen Klinsmann's men the advantage.
And the historic success was achieved after Everton goalkeeper Tim Howard had produced two late saves to deny Mexico's Manchester United forward Javier Hernandez.
It was the second notable victory for the Americans this year, following their first-ever victory over Italy in a friendly at Genoa in February.