Millman will move on to the quarterfinals to face Novak Djokovic, who did his part Monday as he punched his ticket with a 6-3, 6-4, 6-3 win over unseeded Joao Sosa.
Next up for Keys, who was routed by Sloane Stephens in last year's final, is the victor of the evening clash between five-times Grand Slam champion Maria Sharapova and Spanish 30th seed Carla Suarez Navarro.
Stream every match at the US Open live on the FOX+ app and catch up on highlights of any action you've missed. The No. 21 seed from Japan returned to the tour early this year, building his confidence back with a victory in a Challenger Tour event, then reached the final in Monte Carlo and the quarterfinals at Wimbledon, where he lost to eventual champion Djokovic.
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The fourth seeds defeated Albert Ramos-Vinolas of Spain and Argentina's Guido Pella 6-2 6-3 to continue their great form. But it looks like Mohamed Lahyani didn't read the rulebook and Nick Kyrgios was at the receiving end of his favour.
The upset for the ages looked remote when Federer broke Millman - playing his his first fourth-round match at a slam at age 29 - in the second game of the match en route to taking the opening set in routine fashion. He reached the quarterfinals for an 11th consecutive appearance in NY as he bids for a third U.S. Open championship and 14th Grand Slam trophy.
Information from The Associated Press was used in this report. Not simply because Federer lost he entered the day 28-0 at the U.S. Open, and 127-1 in all Grand Slam matches, against foes below No. 50 in the ATP rankings but how he lost.
It was most striking during Lesia Tsurenko's 6-7 (3), 7-5, 6-2 win against Marketa Vondrousova, in which both players seemed affected by the temperature and mugginess.
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Both Ronaldo and Manchester United are struggling at their respective ends. If I say it again now it is not because of two defeats. The Fiver: sign up and get our daily football email.
She finally pulled it out when the No. 26-seeded Sabalenka double-faulted on match point, tossing her racket to the court in frustration.
The third set was a much tighter affair with just one break chance to Federer in the very first game as it went to a tiebreak, Federer squandering a set point at 6-5 before Millman clinched to go ahead point at the second attempt to lead for the first time. Osaka beat No. 26 Aryna Sabalenka 6-3, 2-6, 6-4 to earn her first trip to a Grand Slam quarterfinal.
The 37-year-old second-seeded Swiss will have his work cut out against the 30th-seeded Australian at Arthur Ashe Stadium.
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Sharapova won the 2006 title in NY, but she's now lost in the fourth round in her past three appearances.