Unseeded Borna Coric has ended the US Open campaign of fellow 20-year-old Alexander Zverev in the second round at Flushing Meadows.
Croatian Coric ousted the highly-fancied fourth-seed 3-6 7-5 7-6 (7-1) 7-6 (7-4).
The 61st-ranked Coric screamed in triumph when Zverev sailed a forehand over the baseline to end the match.
It was among 58 unforced errors committed by the German.
"It's upsetting because the draw is pretty open in the bottom part," Zverev said.
"I felt like I should have been favoured there. I just played a very, very bad match, so it's unfortunate. But that's how it is."
Coric moves on to the third round to face 28th-seeded Kevin Anderson of South Africa, a 6-3 7-5 6-4 winner over Latvia's Ernests Gulbis.
Teenager Denis Shapovalov capped off Wednesday's packed schedule with a straight-sets upset of eighth-seeded Jo-Wilfried Tsonga on Arthur Ashe Stadium.
The Frenchman had little answer to the 18-year-old qualifier's shot-making and enthusiasm with the Canadian winning 6-4 6-4 7-6 (7-3).
"I played unbelievable today," Shapovalov said.
"I don't know why but I just managed to stay loose and go for my shots the whole match, except a little bit serving for the third set."
Marin Cilic steamrolled Florian Mayer 6-3 6-3 6-3 to cruise into the last 32, in what is a very favourable half of the draw for the fifth-seeded Croatian.
Next he will face Diego Schwartzman after the Argentine defeated Janko Tipsarevic 6-2 6-4 7-5.
Top-ranked American John Isner served 28 aces in a 6-3 6-4 7-5 victory over Hyeon Chung to be the first player into the third round.
The 10th-seeded Isner will play 23rd-seeded German Mischa Zverev after the German knocked off Benoit Paire 6-3 6-2 3-6 6-7 (3-7) 7-5.
Isner was joined in round three by compatriot Sam Querrey, the 17th seed, who belted Israel's Dudi Sela 6-4 6-1 6-4.
Spaniard Pablo Carreno Busta, the 12th seed, defeated Cameron Norrie 6-2 6-4 6-3, while 16th-seeded Frenchman Pouille needed five sets to overwhelm Jared Donaldson 7-5 6-4 4-6 3-6 6-4.
The seeded players to lose their second-round matches were 19th-seeded Gilles Muller and 20th-seeded Albert Ramos, to Italian Paolo Lorenzi and Frenchman Nicolas Mahut respectively.
Other second round winners were Kyle Edmund of Britain, Mikhail Kukushkin of Kazakhstan and Moldova's Radu Albot.
Earlier in the day, Grigor Dimitrov, David Goffin, Gael Monfils and Juan Martin del Potro were among the seeded men to progress to the second round.
Also advancing to the second round were 15th-seeded Tomas Berdych, 18th-seeded Gael Monfils, Argentina's 2009 US Open champion Juan Martin del Potro, the 24th seed, Adrian Mannarino and Philipp Kohlschreiber.
Seeds Fabio Fognini, Richard Gasquet and Pablo Cuevas were first-round casualties.
Other notable first-round winners included Spanish veteran Fernando Verdasco, Russian Mikhail Youzhny and Alexandr Dolgopolov of Ukraine.
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