The quartet of Jack Alexy, Chris Guiliano, Hunter Armstrong and Dressel came home in 3min 09.28sec with Australia taking silver in 3:10.35 and Italy bronze in 3:10.70.
But they had their work cut after the opening leg with Chinese 100m world record holder Pan Zhanle putting in a scorching two laps.
The dominant Americans hauled themselves back into contention with Dressel powering them to the finish line.
Kyle Chalmers put in a cracking final leg to hand Australia silver, with his 46.59 the fastest split of any swimmer.
The United States have long dominated the event, winning 10 of the 14 times it has been on the Olympic programme before Paris.
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