Play was interrupted in the second set of his contest against Dmitry Tursunov for more than an hour because of rain - but when the players returned eighth seed Isner played the better tennis to win 6-7 (7/9) 6-3 6-4.
The victor said afterwards: "It's my absolute favourite time of the year.
"It's not a coincidence that I play and do well here in the summer, every single year."
The American fired 29 aces, including six in a row in his last two service games to close out the match.
Del Potro, the 2008 and 2009 champion in this event, wrapped up a 7-6 (7/4) 6-3 win over third seed Tommy Haas to make sure of his place in the final.
Rain again intervened in this contest, with Haas on top at 4-1 in the first set when the weather caused play to be suspended at William HG FitzGerald Tennis Center.
The women's final will be between Magdalena Rybarikova and Andrea Petkovic.
Slovakia's Rybarikova was far too strong for Ekaterina Makarova, winning 6-2 6-0 in an hour and 15 minutes.
Meanwhile, Petkovic bounced back strongly after being broken in the opening game of her match against fourth seed Alize Cornet.
The 25-year-old German won the first set in a little under an hour, breaking her French opponent in the 12th game to achieve the feat, and went on to wrap up a 7-5 6-3 win in an hour and 38 minutes.