In a clash between two of the tour's elite servers, and two of the tallest men to ever play professional tennis, break points were hard to come by, and even harder to convert, as Opelka saved all eight opportunities he faced, while Isner saved four out of five.
That one break decided the first set, as 6ft 10in Isner fought back from 40-0 down to force deuce, but the fourth break point of the game was converted by 6ft 11in rival Opelka.
The ATP said their respective heights made it the tallest tour final in the Open Era.
In a match that was always likely to be decided by whoever served best, Opelka had five aces to Isner's two in the first set, while Isner also had the only double fault.
Isner was much stronger in the second set, creating seven break-point opportunities, but he just could not win the important points as Opelka's serve repeatedly got him out of trouble.
Isner then had three opportunities at set point in the tie-break to force a decider, but it was Opelka's day, as he saved all three and converted his first chance at match point.
After dropping a set in his first-round match against Mitchell Krueger, Opelka was perfect the rest of the tournament, beating Gijs Brouwer and Nick Kyrgios in straight sets on his way to the final.