American tennis reached a historic low on Monday when Isner dropped out of the top 20, making it the first time since the rankings began that no US player has been at that level.
But the 28-year-old has answered the critics in the best possible fashion with one of the best weeks of his career.
On Friday Isner stunned world number one Djokovic in the quarter-finals and on Saturday he recovered from a seemingly impossible position to beat seventh seed Del Potro 6-7 (5/7) 7-6 (11/9) 6-3.
Del Potro broke to lead 5-3 in the second set and held a match point but served a double fault, Isner broke back and then took his fifth chance in the tie-break.
The Argentine looked lethargic and could find no way back after Isner won the first three games of the decider.
The 6ft 10in giant will play either Rafael Nadal or Tomas Berdych in the final, and he is taking confidence from his excellent form on home soil this summer.
Isner told Sky Sports: "As of right now I'm just very thrilled to be in the final. I've got to get myself ready and I know it's going to be another tough match.
"I certainly believe I can beat anyone, and if I can take that belief onto the court tomorrow I'm going to give myself a shot."
Isner's first Masters final came in Indian Wells last March, when he also beat Djokovic before losing to Roger Federer.
"I know I'm playing fantastic tennis," said Isner. "Whenever I get back home to the US I always play my best."
Berdych was rewarded with a a semi-final against Rafael Nadal after the Spaniard rallied from a set down to beat old foe Roger Federer 5-7 6-4 6-3.
Nadal extended his winning streak on hardcourts to 13 in 2013 as well as putting himself within two matches of a record-equalling fifth Masters crown this year.
"It was very close," Nadal told atpworldtour.com. "He had a good chance in the second. I think I played a good few points in important moments."
Federer labelled the performance a "step in the right direction" after a relatively lean 2013.
"I'm happy with my progress along the way," Federer said. "Could have won tonight [Saturday], should have won tonight [Saturday], who knows? But at the end, I think Rafa's confidence and the way he's playing at the moment got him through.
"So for me, I think it was a good step in the right direction."
Juan Martin Del Potro beat Dmitry Tursunov 6-4 3-6 6-1 to complete the semi-final line-up.
In the women's draw, top seed Serena Williams comprehensively ended Simona Halep's impressive campaign to set up an intriguing semi-final with defending champion Li Na.
The Romanian's run to the last eight included the victory over Marion Bartoli which sent the Frenchwoman into retirement, but she had no answers against Williams, slipping to a 6-0 6-4 defeat.
Li was handed a walkover into the semis when fourth seed Agnieszka Radwanska withdrew from the tournament to attend her grandfather's funeral.
The other semi-final will be between second seed Victoria Azarenka and Jelena Jankovic.
Azarenka battled past Caroline Wozniacki, the Danish 10th seed, 6-3 7-6 (7/5), while Jankovic was a 6-0 6-4 winner over Italy's Roberta Vinci.