The American managed to pick up a 7-5 6-2 4-6 7-6 victory at Flushing Meadows, in a match that witnessed the New York crowd rhythmically clapping while chanting, "Let's go, Monfils!" throughout its duration.
Despite being pleased to see the Frenchman back in action after recovering from injury, Isner admits that he was disappointed by the supporters during the match.
"I was a little bit disappointed in that, actually. Not going to sugarcoat it," said Isner, according to The AP. "If I was playing in France, it certainly wouldn't be like that.
"He's a very fun-loving guy, and he gets cheered on wherever he goes, not just in France. He's one of the most exciting tennis players in the world, hands down.
"He's been fighting a bunch of injuries, so it's good to see him back healthy."
Isner moves into the third round for the fifth consecutive year.