Juan Martin del Potro announced his decision to miss the tournament after his defeat to American MacKenzie McDonald in the quarterfinals of the Delray Beach Open in Florida.
Del Potro's career has been beset by injuries and a long period on the sidelines saw his career ranking plummet to 1,045th place in 2016.
Federer, the defending champion, beat Daniil Medvedev 6-4, 4-6, 6-4 in the second round despite being broken late in the second set.
Hearing those delirious Argentine fans sing "Ole! Ole! DelPo!" again between points, gave him something else rewarding to take home from Flushing Meadows.
A year after missing the U.S. Open because of an injured right elbow that would require surgery, Djokovic showed that he is unquestionably back at his best and back at the top of tennis.
On Sunday, No. 3 del Potro will face No. 6 Novak Djokovic, who advanced with an emphatic 6-3, 6-4, 6-2 victory over No. 21 Kei Nishikori in the second semifinal.
Del Potro was leading 7-6 (3), 6-2 after two hours of play when Nadal shook his head and said he had to stop.
All four players have reached the U.S. Open final while only Nishikori hasn't won it to make this the first Grand Slam final four since the 2012 Australian Open in which all four players were past finalists.
The top-seeded Halep's exit means only one of the women's top-10 seeds remains in the tournament, Pliskova, which leaves Serena Williams as the big favourite to win her eighth Wimbledon title.
The No. 1-ranked Nadal compiled a 35-20 edge in winners while making only 19 unforced errors on Friday.
Del Potro is playing in the French Open semi-finals for the first time in nine years.
With his good run at Roland Garros, Del Potro is now guaranteed to return to the top four in the rankings for the first time in more than four years.
Dominating with his serve and aggressive baseline strokes, the 6-foot-10 Isner ended a 15-match winning streak for del Potro, who won Indian Wells two weeks ago by beating Roger Federer in the final.
Argentina's Juan Martin Del Potro jumped to sixth place after he stunned Federer 6-4, 6-7 (8), 7-6 (2) to win his first Indian Wells title on Sunday.
The win ranks right up there with Del Potro's 2009 U.S. Open title triumph, in which he beat Federer, and helping Argentina win the Davis Cup in 2016.
The 29-year-old Argentine star beat three straight players ranked ahead of him in the hard-court event, topping No. 6 Dominic Thiem in the quarterfinals, No. 5 Alexander Zverev in the semifinals and eighth-ranked Anderson in finals.
Matches weren't halted Thursday as the highs stayed just below 40 Celsius for much of the day, but that doesn't mean the heat didn't cause issues for the players.
Isner will next face Serbian qualifier Filip Krajinovic, who advanced when Nadal withdrew.
Melbourne: Juan Martin del Potro's injury time-off from Grand Slam tournaments just got a little longer.The 2009 U.S. Open winner withdrew Sunday from the Australian Open on the eve of the tournament to avoid re-injuring
Canberra: Former chas withdrawn from the Brisbane International, officials said Thursday, further delaying his return to the court from an injury-blighted 2014.The Argentine had been scheduled to play in the Jan 4-11 Brisbane event, ahead
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