The Canadian enjoyed some better moments towards the end of the second, but it wasn't enough to dislodge the three-time Miami champion who now has a chance to land his 101st career crown after missing out in Indian Wells where he lost to Dominic Thiem in the final. Isner injured his foot during the first set, continued to play, but his movement was limited in the second set. He broke in the opening game and then twice more in a first set that lasted only 24 minutes.
But the American fought back in the second, levelling the set 3-3 and 4-4 before the pain made it hard to continue.
"It was a dream start, relaxing my nerves", the Swiss, 37, said in a courtside interview.
"Somewhere during the first set I started feeling pain on top of my foot and it didn't go away and it just got worse", Isner said. "I had to", Federer said.
Isner's serve is regarded as one of the most potent weapons in the game, but it was Federer who continually held easily on Sunday as he secured his fourth title in Miami and the 101st of his career.
Federer paid tribute to his opponent's determination after the match.
Isner first appeared to be bothered by his foot in the seventh game of the second set.
Federer would look to overpower Isner's deadly serves.
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And so far this year, Isner is a ideal nine wins from nine in the tiebreakers he has played - with nine of the 10 sets he has played in Miami Gardens having been decided by one. Federer took the final two games for the victory.
"If I'm Isner's coach I'm saying, 'Focus on your serve, take risks on the return and anything can happen'".
"He's definitely got one of the serves that you basically can't read".
In conclusion, Roger Federer said, "But I still think they all will be back this year at some point, hopefully, and the year-end hopefully will be incredibly exciting".
Roger Federer of Switzerland poses with the trophy after defeating John Isner of the United States (not pictured) during the men's finals at the Miami Open at Miami Open Tennis Complex.
"I'm hoping to see some tiebreakers in that final and I'm sure John knows that as well".
It was the first meeting between the pair and while Shapovalov gave it his all, Federer was simply incredible at the ATP 1000 tournament.
"It was hard for John at the end", Federer said.