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.
The Americans, who were reigning champions, had their work cut out after the opening leg with Chinese 100m world record holder Pan Zhanle putting in a scorching two laps.
But the US 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.
China, who are competing under a doping cloud, finished out of the medals in fourth.
The United States have long dominated the event, winning 10 of the 14 times it has been on the Olympic programme before Paris.
For Dressel, 27, it was his eighth gold medal from three Olympics, and he was tearful in the celebrations.
"I mean, you can't help it. You can't explain this moment. So you're on the podium watching the flag go up. Hunter (crying) actually happened before the flag went up. So it's really special seeing that," he said.
Dressel won five golds in Tokyo three years ago but took time out from the sport before coming back in time to qualify.
He appreciated seeing his younger team-mates Guiliano and Alexy win their first Olympic golds.
"I remember how it was for me with my first gold. I mean, I lost it."
"No one can take that away from us," he added.
There was more emotion for Dressel when he was able to celebrate with his wife Megan and their baby son August.
"It's really special, making the team in front of them and then winning a gold in front of them. Just checking little boxes that I never would have thought to create throughout my career," he said.
