The 37-year-old world five bankrupt in the opening game and took the first set in 2-4 minutes.
Inside his 50th Masters final, the SWISs fourth seed produced several on average sublime groundstrokes and wrapped up the game in an hour and three minutes.
It’s that his 28th Masters title and the 101st entire for a player that has won 20 Grand Slam singles titles.
Isner came into the first meeting between the pair in Miami having never dropped a pair through the entire championship, winning two of the 10 places in the process by tiebreak.
Federer had won all four of these previous matches on hard courts and claimed that his dominance from the outset.
Seventh seed Isner had treatment on his left foot in 43 down in the second group however, the game was soon delivered to its decision as Federer improved his overall record against the angular, 6ft 10in (2.08m) American to six wins in eight matches.