Isner's serve is regarded as one of the most potent weapons in the game, but it was Federer who continually held with ease as he secured his fourth title in Miami and the 101st of his career.
The runner-up to Dominic Thiem at the Indian Wells Masters earlier this month, Federer won a remarkable 21 points in a row on serve at one point, leaving his opponent powerless.
Having been broken three times in the opening set, Isner put up more of a fight in the second and initially kept pace with Federer only to suffer an injury to his left foot.
Isner could hardly move as he attempted to hold trailing 4-5 and it was no surprise to see Federer break to seal an emphatic victory.
Federer ended the contest having won 32 out of 35 points on his serve. A champion in Dubai earlier this month, the veteran Swiss is the first player to claim two titles on the ATP Tour in 2019.
In the post-match presentation, a gracious Isner said to Federer: "You were entirely too good today; you were entirely too good this whole tournament; you were entirely too good in your whole career.
"It's absolutely incredible what you're doing. We're so lucky to have you in this game and we all want you to keep playing and literally never retire."