Wu, 23, held off four match points before going on to secure a 6-7(4-7) 7-6(7-3) 7-6(14-12) win over American Isner, a man with 16 titles, in just under three hours.
Before his run to the final, no Chinese man had ever reached a tour-level final in the professional era or defeated a top-10 opponent.
In beating world number eight and top seed Taylor Fritz in the semifinals, the Hangzhou native had already made his mark in the history books by achieving both those feats.
And on Monday he continue to set records when he rose to world number 58 in the rankings, making him the highest-ranked Chinese player in ATP history.
“I made history here for my country and for my home,” said Wu at the trophy ceremony. “I’m very proud of myself and especially thanks to all the fans and my team who came here to support. I couldn’t do this without any of you guys.”
The big serving Isner served a remarkable 44 aces in the match, which lasted two hours and 59 minutes.
In the final tiebreak, 22 consecutive points went with serve before Wu forced Isner to hit a forehand long.
“I don’t know how many match points I had, I’m sure it’s a lot,” said Isner. “I swear I thought I won the match a few times … Sports can be brutal.
“He is an unbelievable ballstriker and a very good talent.”
Prior to this week, Wu — who had not competed on the tour from March 2019 to January 2022 because of injuries — had won just six tour-level matches.
In Dallas, he beat a series of high-caliber players in Michael Mmoh, Denis Shapovalov, Adrian Mannarino, Fritz and Isner.