Jonathan dos Santos was the hero for El Tri with the 73rd-minute winner at Soldier Field in Chicago.
Dos Santos took his chance excellently in a game during which the USMNT squandered theirs, with Christian Pulisic and Jozy Altidore missing early opportunities.
Jordan Morris also had a header cleared off the line before Dos Santos' winner came after a period of dominance by Gerardo Martino's men.
USA made a brilliant start and created two great chances in the opening eight minutes.
The first opportunity fell to Pulisic, who was denied in a one-on-one by Mexico goalkeeper Guillermo Ochoa after being set up by Altidore.
Altidore should have opened the scoring for USA soon after, but he scuffed an effort wide after a wonderful change of direction on the edge of the area.
Mexico responded and almost took the lead through Andres Guardado, who blazed over from inside the area under heavy pressure from Paul Arriola.
In what was a frantic end-to-end first half, Arriola fired another decent chance wide for USA from inside the area.
USA continued to enjoy the better opportunities to begin the second half, with Morris' 51st-minute header from a corner cleared off the line by Guardado.
Mexico were much-improved after that chance, enjoying a good period that included Jesus Gallardo directing a 25-yard volley straight at USA goalkeeper Zack Steffen in the 68th minute.
And they capitalised on their period of dominance with the opener just five minutes later through Dos Santos' third international goal.
A fine move down the right led to Raul Jimenez back-heeling a pass into the path of Dos Santos, whose excellent left-footed effort went in via the underside of the crossbar from just inside the area.
That would prove to be enough for Mexico as they saw out the closing stages to secure the title.
CAMPEONES!🏆🇲🇽— FOX Soccer (@FOXSoccer) July 8, 2019
Mexico captain Andres Guardado lifts the Gold Cup! pic.twitter.com/f3U1wr04rZ
What does it mean? Mexico pull clear
While USA had the better of the chances, Mexico's win marked their eighth Gold Cup crown. That moved them two titles clear of USA, who have won six.
Mexico extend their lead over the U.S. in all-time Gold Cup titles 📈🏆 pic.twitter.com/SnIJW4QOqP— FOX Soccer (@FOXSoccer) July 8, 2019
Martino delivers for Mexico
Mexico impressed after Martino took charge in January, although their performances in the knockout stage of the Gold Cup never reached any great heights. Still, the Argentinian helped deliver the title for Mexico.
USA left to rue missed chances
The hosts dominated long periods without capitalising and they were made to pay. Pulisic and Altidore missed good chances and Morris had another cleared off the line, while Mexico saw their period of dominance capped off with Dos Santos' winner.
USA are looking ahead to the CONCACAF Nations League in October, while Mexico will face Argentina in a friendly in September.