The big-serving 32-year-old has endured his fair share of misery in Masters 1000 finals, however he refused to let his fourth bid for glory end in another hard-luck story.
Isner became the first non-European to triumph at Crandon Park since Andy Roddick in 2010 after a spirited 6-7(5) 6-4 6-4 success over Alexander Zverev.
It’s the biggest win of his 11-year career, and he capitalised on a golden opportunity to win a much-craved second tier title.
He could have prevailed more convincingly than he did – converting just two of 12 break-points chances – but the tension and uncertainty only added to his eventual satisfaction.
Isner could barely contain his excitement after firing down his 18th ace on his first match-point – and he revelled in the adulation from the appreciative crowd. His victory will see him climb back inside the Top 10 on Monday.
“To win like that in front of a crowd like that, with that atmosphere, you can't replicate moments like that,” said the new champion. “It was absolutely amazing.
“This tournament has so much history. All the best players have played here thought the years. For Sascha and I to share the court in the last men's singles match ever here at this tournament is amazing. I never thought I would be in this moment considering how I was playing coming into this event.”
Zevrev’s quest for a third Masters crown, 19 days prior to his 21st birthday, ultimately ended in disappointment, but he will be encouraged by his performances and results in the Sunshine State after a stuttering start to the campaign.
In soaring temperatures, it was Isner who made the brighter opening. He swung freely and performed on instinct, however he failed to turn his superiority into something tangible on the scoreboard.
The American was repeatedly denied as he attempted to nudge ahead, and a tiebreak was eventually reached. At 4-4 in the shootout, Isner committed a double-fault to gift his rival the lead and eventually the set.
Zverev exploded with joy after sealing the opener and another milestone win was within his grasp. The second set was less frantic, though, as both players held serve without too much difficult.
With the checkered flag in sight, Zverev faltered. At 4-4 on the German's serve, Isner clubbed a trademark inside-out forehand winner, which caught a tiny portion of the line, to nab the first break of an absorbing duel.
There was a rare outpouring of emotion from Isner as he celebrated a pivotal breakthrough, but he still had to endure a torturous service game – filled with scintillating rallies – before squaring the tie.
The unrelenting heat took it’s toll on both players in the decider, and Isner did not make his domination count until the ninth game. Zverev slammed a weary-looking forehand into the net to fall a break behind before obliterating his racket in disgust.
Isner brought the curtain down on the Miami Open with a flurry of winners, and he was soon holding aloft the trophy he had worked tirelessly to earn.