Marin Cilic's defeat to Diego Schwartzman means there will be a first-time finalist in the men's draw. Meanwhile, it was a good day for the Williams sisters, with a win for Venus and a new arrival for Serena.
Cilic, the fifth seeded Croatian who won the event in 2014, struggled with an adductor strain throughout as Schwartzman progressed 4-6, 7-5, 7-5, 6-4.
"[The injury] played a quite significant part, and just being injured and not being able to keep that good form," Cilic said. "I was struggling with my shots and my serve was off."
His exit ensured a first-time Slam finalist will come from his half of the draw, which has no top 10 players remaining. Both Federer and Nadal are in the other half of the draw and are on course to meet in the semifinals.
Shapovalov profits from Edmund misfortune
Injury also played a part in the other notable result in the men's draw. Canadian teen Denis Shapovalov became the youngest man since 1989 into the last 16 at Flushing Meadows after Britain's Kyle Edmund retired with a neck injury with the Canadian leading 3-6, 6-3, 6-3, 1-0.
"It's never great to win this way. Hopefully it's nothing too serious," said Shapovalov. "It's very unfortunate but at the same time I'm happy to be in the fourth round."
Shapovalov will play Spanish 12th seed Pablo Carreno Busta in the next round, while Schwartzman plays Lucas Pouille.
Great day for the Williams sisters
Venus Williams was beaming even before she hit her first serve as the seven-time Grand Slam champion and new aunt confirmed reports of her sister's new child before walking onto the court for her third-round match against Greece's 95th-ranked Maria Sakkari.
"Obviously I'm super-excited," US ninth seed Venus said. "Words can't describe it."
The 37-year-old made short work of her opponent, winning 6-3, 6-4. She'll be joined in round 4 by Garbine Muguruza, who beat Venus in this year's Wimbledon final. The Spaniard needed only 62 minutes to dispatch Slovakian 31st seed Magdalena Rybarikova 6-1, 6-1 to continue her best US Open run.
mp/jh (Reuters, AFP)