Isner, who was sidelined by a stress fracture in his left foot for three months after reaching the Miami final in March, was the top seed in the tournament that he also won in 2011, 2012 and 2017.
Bublik, the seventh-seeded 22-year-old from Kazakhstan who was playing in his first ATP final, double-faulted on break point to fall behind 3-2 in the second set, and that was the only opening the big-serving Isner needed.
The 34-year-old American -- who produced only a modest five aces but put 79 percent of his first serves in play -- finished off the match with a forehand winner even as he slipped on the grass and sprawled forward.
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He converted all three of his break points in the game, including on match point when the Kazakh failed in his bid to catch Isner out with an underarm serve on the final point.
While that didn't pan out, Isner urged Bublik to continue to pursue his "quirky" game.
"It was a lot of fun to play against you today," Isner told him. "You're very quirky, but I mean that in a very sincere way.
You're fantastic for the game and we all hope you continue to have great results in the future because guys like you are important to keep tennis exciting."
The towering American also had words of thanks for his team, especially his physical therapist.
"It's not easy keeping a guy like myself healthy," said Isner, who is slated to appear next week in Atlanta, Georgia, in search of a sixth title in the BB&T Open.
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Bublik, who has toiled largely on the ATP Challenger Tour, is assured of reaching a career-high ATP ranking on Monday, when he will break into the top 75 for the first time.
Bublik had earned the first break of the match at 5-5 in the opening set, but he double-faulted on break point in the next game as it went to a tiebreaker that Isner dominated.
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