Pablo Barrera scored his second goal of the game in the 50th minute to break a 2-2 deadlock and Giovani Dos Santos added an insurance goal in the 76th minute for the Mexicans, who trailed 2-0 after only 23 minutes.
"There's no better moment than victory," Mexico coach Jose Manuel de la Torre said. "Everything else is in the past now."
Mexico on Saturday won their second title in a row in the biennial North American regional tournament, defeating the United States in the final as they did in 2009, and qualified for the 2013 FIFA Confederations Cup.
Mexico's Javier Hernandez, who plays for Manchester United in the English Premier League, was named the Gold Cup Most Valuable Player. Hernandez led this year's tournament with seven goals.
Mexico and the US team have won 10 of the 11 Gold Cups contested since the tournament took its current form in 1991.
Dos Santos netted one of the prettiest goals of the tournament, dancing around US goalkeeper Tim Howard, who had charged out of his net after a loose ball, then spun past two stunned defenders and chipped the ball over a leaping Eric Lichaj into the upper right corner of the net.
The Americans played well defensively in the tournament until they came up against the explosive Mexican attack. American captain Carlos Bocanegra said there was confusion among the US defenders Saturday.
"It was an overall frustrating night," Bocanegra said. "Defensively we weren't good enough."
A sold-out crowd of 93,420 at the Rose Bowl was the largest ever for a Gold Cup game in the USA. The pro-Mexican crowd was clad mainly in green and cheering loudly for the visitors despite the match being played on US soil.
American fans tried to get chants of "USA, USA" going in the first half but they were quickly drowned out by the "El Tri" supporters with a chorus of "Ole, Ole".
Michael Bradley scored in the eighth minute and Landon Donovan added another goal in the 23rd minute as the Americans jumped out to a 2-0 lead. Donovan's goal was his 13th in Gold Cup play, giving him the all-time tournament lead.
"You're worried and you don't want to become disorganized," de la Torre said. "The United States was playing well. They surprised us with the first goal. We pushed too far up in the second goal. Fortunately, we were able to maintain our calm."
Barrera then scored his first goal in the 29th minute and Andres Guardado, who was playing with an injured left ankle, netted the equalizer in the 36th minute, setting the stage for a second half dominated by the Mexican squad.
Barrera put his 17-yard shot just inside the right post to snap Howard's tournament shutout streak at 351 minutes.
Guardado tied it by pouncing on a loose ball about five yards out to tie after Dos Santos started the play with a pass from the right side that bounced off Lichaj.
"Our back line couldn't figure it out," Bocanegra said. "They spread us out and we weren't all on the same page."