The American was impressive not only in dealing with the threat of a unpredictably talented Frenchman, but also a strangely partisan crowd at Flushing Meadows.
A close first set went with serve until Isner broke through as Monfils looked to force a tie-breaker.
However, the second set was a much more straightforward affair for the 28-year-old from North Carolina, who took 32 minutes in wrapping it up 6-2.
Monfils finally broke Isner in the third set, which was enough to see him edge it 6-4 and reduce the deficit to one.
The fourth set was another tight one, which this time went to a tie-breaker. Despite many in the crowd chanting for Monfils, Isner managed to hold his nerve to blast his way to a 7-4 victory.
Victory means that he will play Germany's Philipp Kohlschreiber for a place in the fourth round in New York.