Zheng Qinwen won the last seven games to stun Madison Keys and reach the US Open last 16 on a Saturday of upsets that dented American hopes at Flushing Meadows.
Fourth-seeded Coco Gauff battled through in straight sets, and 18-year-old US compatriot Iva Jovic held off Philippines sensation Alexandra Eala in three sets.
But Americans were hard hit with ninth-seeded Taylor Fritz and 2025 finalist Amanda Anisimova following Keys out the door.
Fifth-seeded French Open finalist Flavio Cobolli of Italy also fell to 21-year-old Alexander Blockx.
Zheng saved a match point in her 1-6, 7-6 (7/3), 7-5 triumph over Keys, the 2025 Australian Open champion and a US Open finalist back in 2017.
After coming through the second-set tiebreaker, the Paris Olympics gold medallist appeared to be out of steam in the final set.
The former world No 4 had to come through qualifying after a lengthy recovery from elbow surgery saw her ranking plummet.
Keys raced to a 5-0 lead in the third but Zheng had a last stand in her.
She saved match point at 5-1 and just kept rolling, Keys' increasing frustration showing as she banged her head with her racquet after one lost point.
"I just told myself keep holding every single point, never give up, stay there. And somehow, little by little, it just happened," Zheng said.
Zheng, currently ranked 121st in the world, will face six-time Grand Slam champion Iga Swiatek for a place in the quarterfinals.
Swiatek saved three set points in the second set, dominating both tiebreakers in her tight 7-6 (7/3), 7-6 (7/3) win over Czech Maria Bouzkova.
Belgium's Blockx shocked Cobolli 6-7 (4/7), 6-3, 6-0, 6-3, winning 11 straight games from 3-2 down in the second set as he reached the second week of a Grand Slam for the first time.
"I think this was one of my craziest experiences so far in my career," Blockx said after firing 17 aces past Cobolli.
Blockx next faces Francisco Cerundolo, who rallied from two sets down to upset ninth-seeded Fritz 3-6, 4-6, 6-3, 6-4, 6-4.
Down 4-3 on serve in the final set, the 24th seed from Argentina fought back from 0-40 down to hold, coming up with a trio of booming serves and a thundering forehand before taking the game with another service winner.
He then broke Fritz and cruised home.
Austrian Anastasia Potapova ended Anisimova's run with a 6-2, 7-5 victory.
Potapova is into the US Open last 16 for the first time where she will face fifth-seeded French Open champion Mirra Andreeva, who beat Nikola Bartunkova 6-2, 7-6 (7/5).
ZVEREV UNDER THE LIGHTS
Former champion Gauff shook off a slow start to beat Spain's Cristina Bucsa 6-3, 6-4, relying on her defensive skills as she climbed out of a 3-1 hole in the opening set.
"She's a tricky player, so it's tough to get rhythm," Gauff said. "Happy with how I fought through even when I wasn't playing my best."
Gauff said the US exodus didn't affect how she approached her match.
"Upsets are a thing, but at the end of the day, anybody can lose," she said.
"I go into it with that mindset ... it makes me have my guard up all the time, which makes me play better."
Gauff next takes on Jovic, the 14th seed who won the duel of rising stars with 17th-seeded Eala 7-5, 3-6, 7-5.
Jovic rallied from 4-2 down in the third set to improve to 3-0 against her friend and sometime doubles partner.
Their three-hour tussle meant men's top seed Alexander Zverev didn't take the court to face Chile's Alejandro Tabilo until nearly 11:00 pm.
In two five-set matches, both spilling into the early hours of the morning, the German has already spent nine hours and 26 minutes on court.
Zverev says he feels fine physically, but he knows he will have to play better if he wants to add a second Grand Slam title to the French Open trophy he captured this year.