Jack Sock knocked 2014 champion Marin Cilic out of the US Open in the third round on Friday, handing the seventh seed a 6-4, 6-3, 6-3 surprise.
Top-seeded holder Novak Djokovic benefited from a second straight pullout as Mikhail Youzhny quit after 31 minutes trailing 4-2 and favouring his back.
Djokovic got a free ride to the third round 48 hours earlier when Jiri Vesely withdrew injured before their match and an inflamed forearm.
The Serb moved to the New York fourth round for a 10th straight year.
Croatia's Cilic came to the final major of the season in top form after breaking through last month for his first career Masters 1000 title in Cincinnati, as he beat Andy Murray.
US player Sock stuffed any chances for the seventh seed with his victory; Cilic had won 18 of his last 20 matches at the US Open.
"For me to make the second week here and every slam going forward is my goal. I feel like if I'm playing good tennis and how I can, I feel like that's kind of where I belong," Sock said.
"I was able to piece it together today well and play a good match. Always happy to get through the next round, but definitely the hunger and excitement is that much and more. Every round you make you want to keep going and keep playing good tennis, especially in front of your home fans."
Sock drove home a point he made last season in Davis Cup play against Cilic, when he recovered from a two-sets-to love deficit to earn a win in their only previous meeting.
Sock has now reached the fourth round of a grand slam for the second time after doing so last year at Roland Garros.
Ninth seed Jo-Wilfried Tsonga dispatched South African Kevin Anderson 6-3, 6-4, 7-6 (7-4), then put on a shadow boxing display in the style of the late Muhammed Ali.
The Frenchman now leads 3-0 in the series after winning his 27th match of the season. Tonga has twice reached the New York quarter-finals.
"It's never easy to play that kind of player. He's serving well, he's also moving well from his baseline for his height," Tsonga said. "Today was a good challenge for me to beat him. I did it well, for sure."
French 10th seed Gael Monfils joined in, moving to the weekend 6-4, 6-2, 6-4 over Nicolas Almagro.
2015 women's finalist Roberta Vinci advanced past German Carina Witthoeft 6-0, 5-7, 6-3, while American eighth seed Madison Keys overcame Naomi Osaka of Japan, 7-5, 4-6, 7-6 (7-3).
Lesia Tsurenko of the Ukraine beat 12th seed Dominika Cibulkova 3-6, 6-3, 6-4.
British 13th seed Johanna Konta kept up her breakthrough 2016 progress with a 6-2, 6-1 hammering of Switzerland's Belinda Bencic.
Double Wimbledon champion Petra Kvitova took out Elina Svitolina 6-3, 6-4.
Former number one Caroline Wozniacki continued her own comeback progress as the Dane erases a first half to forget this season; she beat Monica Niculescu 6-1, 6-3 to move into the fourth round of a grand slam for the first time since a year ago at Wimbledon.
"It's been a good week so far. I'm excited to have gotten so many matches on Ashe," Wozniacki said.
"I'm happy to be here just being healthy and playing well. I'm not that worried about the ranking at this point."