Again sporting a freaky hairstyle that he has said was the result of a lost bet, Fognini won 61 of 108 total points (56 percent) while converting all four of his opportunities to break Del Potro, who had won the only previous tournament matchup between the pair.
Del Potro will face second-seeded Fabio Fognini of Italy, a 6-4, 6-2 victor over British left-hander Cameron Norrie in the first semifinal.
The "Mexican Double" will have to wait till next year.More news: Melania Trump praises LeBron James hours after Donald Trump's online swipe
This is the 31-year-old's eighth ATP Tour victory in his career.
The 21-year-old defending champion did not face a single break point as he overcame his Greek opponent 6-2 6-4 in an hour and 28 minutes.
"Fabio deserved to win".
Fognini, ranked 15th in the world, claimed hard-court event for his third victory of the year, with the other two on clay in Bastad and Sao Paolo. He played a very smart game.More news: Britain plans for opt-out organ donation scheme to save lives
"It's wonderful... He's one of the best players... But in many ways I'm looking forward to keep playing better and better in the next tournaments", Del Potro said.
Fognini, who also enjoyed a first round bye, began his tournament with a comeback win against Frenchman Quentin Halys who he defeated 2-6 6-4 6-0 to reach the quarterfinals. So I am really happy about my performance...
"It's something odd because, of course, at the beginning of the week if you told me that we would be talking about titles... well, I am really happy, happy about this week, about my game. Of course, it means a lot for me".More news: Scientists Spot Massive Rogue Planet Just Outside Solar System