Substitute winger Brek Shea scored the only goal of the match after 68 minutes as the Americans claimed the regional championship for the fifth time.
Brek Shea broke through with the only goal of the game in the second half to give the United States their first Gold Cup title since 2007 and make up for back-to-back defeats to Mexico in the last two finals.
While they were thrilled with the result, the Americans hope it is also a springboard to the 2014 World Cup in Brazil.
"Hopefully this is just the beginning for a lot of us," Landon Donovan told reporters. "We want to be a part of the bigger picture. This is not the end."
The win was the 11th in a row for the United States and came without manager Juergen Klinsmann, who was serving a one-game suspension after being ejected in the semi-finals.
The United States had outscored their opponents 19-4 in their five games leading up to the final but Panama, who eliminated Mexico in the semi-final, proved a serious test for the home side at Soldier Field in Chicago.
The United States had much of the possession but were unable to make it count until the 69th minute when Donovan set up the game-winner for Shea.
Donovan, who was named the tournament's most outstanding player, has played his way back into Klinsmann's plans and finished the Gold Cup with five goals, to tie team mate Chris Wondolowski and Panama's Gabriel Torres.
U.S. midfielder Stuart Holden exited the match with a knee injury during the first half. Holden has a history of knee problems that includes multiple surgeries.
Panama's Jaime Penedo, who allowed just four goals in five games, was named the tournament's top goalkeeper for the second time.
"We were all hopeful, we all wanted to win," said Panama coach Julio Dely Valdes. "But we all go away feeling we gave it our all. I said I wanted to walk away from the Gold Cup feeling good, and I do."