The 2.08 metre (6ft 9in) Isner defeated Belgian Olivier Rochus 6-3, 7-6 (8/6) on Newport's grass courts.
Isner, who didn't drop a set all week, closed out the match with his 22nd ace.
"I just served excellent, he said. "I was just fortunate to have that weapon. I was in a groove all of my matches. It's huge. I was very lucky to have that serve and it carried me to the championship."
The 30-year-old Rochus is the shortest player on the ATP Tour at 1.70 metre (5ft 6in). He tried to use a mixture of powerful groundstrokes, slicing volleys and speed but couldn't overcome Isner's size and power.
The crowd chuckled on a few serves when Isner bounced the ball all the way over Rochus' head.
"It was perfect serving conditions for me, this court, this tournament," Isner said. "I was surprised how much it was kicking on this grass."
Before the match the pair joked about the height differential by posing for a photo in which Isner patted his opponent on the head.
It was the second career ATP title for Isner, following his win last year in Auckland.
Rochus, who is ranked 74th in the world, said Isner doesn't get enough credit for his all-around game.
"John was a top-20 player in the world," Rochus said. "He can control the ball, he slices. He's a lot more than the serve."
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