The in-form Swiss battled through a flu bug throughout the week to claim his third straight title on the ATP Tour, following on from his recent successes in Rotterdam and Dubai.
"Sometimes just have to play a bit sick," he said. "I am happy to come through at the end. It makes me really happy beating the best. This is a great feeling.
"It has been a tough week with a lot of players getting sick. I am happy I survived the early rounds to give myself a chance."
Having stunned world number one Novak Djokovic in the semi-finals, Isner suggested he could pull off another upset during a tense opening set that included a brief delay for rain.
The big-serving American survived a break point in the 12th game to force a tie-break, Federer eventually coming out on top at the fourth attempt when he forced his rival to hit a backhand long.
The second set went with serve until the seventh game when Federer unleashed a trademark backhand pass down the line to go 15-40 up before Isner netted a backhand volley on the next point.
The 16-time grand slam champion held serve to move 5-3 ahead and then broke again to seal victory after one hour and 21 minutes on court.
"I certainly played well all week and obviously today it did not go my way," Isner said afterwards. "I don't really feel like I necessarily I played my best, but that's what Roger does.
"I mean, if I have any shot to beat him I'm going to have to play my best. That wasn't the case today. He was too strong."
Federer's triumph means he moves level with long-time rival Rafael Nadal, who he knocked out in the semi-finals, on 19 Masters titles.
He has also now won 15 matches in a row, with his last defeat coming against Isner in Davis Cup action. The only other man to beat him in 2012 is Nadal.