Reilly Opelka beat the veteran tennis player 6-3, 7-6 (9-7) for his fourth ATP Tour title and his maiden Tour title on clay.
With his 6-3, 7-5 victory, the American advances to his third tour-level final of the season, all of which have taken place on American soil.
It will be the sixth time Opelka and Isner meet and the match promises to be a fine encounter of youth against experience.
The World No. 13 American won his first clay-court match of the season on Thursday, defeating Alejandro Tabilo 6-1, 6-4
In what was his first clay appearance since Rome in 2019, Kyrgios took some time to find his footing, playing his unique brand of tennis.