Though Nadal's status as world No. 1 and top seed theoretically put him out of reach of the 24th-seeded del Potro, the Argentine is one of only two players - Novak Djokovic is the other - to have beaten Nadal and Federer in the same Grand Slam event.
The current World No.1 player made a staggering win with 4-6, 6-0, 6-3, 6-2 against the Argentina player on Friday.
Talking about his build-up to the US Open, Federer added: "I think there's definitely things that happened in the preparation and throughout the tournament that led to my performance today, because I can play much better but I can play worse, too".
Looking ahead to his semi-final against Nadal, the Argentine 28th seed said: "Against Rafa, hopefully I can repeat the result". But it will be very important for me as quickly as possible to really try, as much as I can, to block that out. "I know that if I play my best tennis I can be a danger to him".
Nadal has won all four of their previous meetings, Anderson managing just a single set, but the Spaniard is wary of his opponent's aggressive game.
The 203cm Anderson, who won a NCAA doubles title at the University of IL, is equipped with a big serve, certainly, but a slam singles final is foreign territory. Look below and find out what you need to know, so you can live stream the U.S. Open semi-finals on your PC, TV, tablet or mobile device.
"It's been a long road", Anderson, who overcame a right hip injury a year ago that had threatened his 2017 campaign, told reporters.
Federer entered the quarterfinals undefeated in Grand Slam play this season. No man has won the U.S. Open without dropping a set in the Open era, which started in 1968. The Swiss is 3-0 against Nadal this year, including his five-set thriller in the Australian Open final.
In a quarter-final match pitting a 15-time Grand Slam champion against an unseeded 19-year-old making his first appearance on a big stage, Nadal's experience proved to be a decisive factor on Wednesday, reports Efe. This year, Del Potro's run in Flushing has been nothing short of remarkable.
"Rafa just played even better the last three sets of the match", Del Potro said.
Juan Martin Del Potro has done it once so why can't he do it again?
"He played so smart from the second set until the end of the match", del Potro said. I have to get ready; still obviously a very hard match ahead of me. But del Potro's toughest career opponent has been his own body: His frequent wrist injuries have prevented him from disrupting the dominance of the Big Four, limiting him to 10 total matches in 2014 and four in 2015.
Del Potro took that opening set, but Nadal took over the match from there.