Serena Williams and Marin Cilic both survived third round scares on Friday to keep their US Open title defences on track but there was no escape for Rafael Nadal with the twice-winner going down in a late night thriller.
A day of riveting high drama began in the early afternoon heat with the ninth seeded Cilic needing over four hours to put away Kazakhstan's Mikhail Kukushkin 6-7(5), 7-6(1), 6-3, 6-7(3), 6-1 and ended in the early morning hours with Italian Fabio Fognini winning a pulsating third round slugfest over Nadal 3-6, 4-6, 6-4, 6-3, 6-4.
In between the two epic battles there was even more suspense as Williams came back to score a 3-6, 7-5, 6-0 victory over Bethanie Mattek-Sands to keep alive her quest to for a calendar Grand Slam.
Williams, who dropped just nine sets, including seven first-set losses, in her charge to the Australian, French and Wimbledon titles, was tested at Flushing Meadows by her fellow American, but roared back to victory to reach the fourth round.
"I'm not trying to live on the edge," the 33-year-old Williams said. "I'm playing players that come out really strong. I just think Bethanie played really well."
The 21-times Grand Slam singles winner, who is aiming to join Maureen Connolly (1953), Margaret Court (1970) and Steffi Graf (1988) as the only women to sweep the four Grand Slams in a single season, next faces another American Madison Keys.
The real fireworks, however, came in the evening as Nadal and Fabio Fognini lit up the New York night with spectacular rallies and winners that had the Arthur Ashe Stadium crowd on their feet well after 1:00 AM.
"If you want to play against him you want to do something different, you have to risk," said Fognini. "That's the only thing.
"Probably I made a lot of unforced errors, but it doesn't matter.
"You have to do that with a great player that runs a lot on the baseline. He's one of the best players in the world."
The defeat ended eighth-seeded Rafael Nadal's streak of 10 years in a row with at least one Grand Slam singles title after the Spaniard lost in the quarters at the Australian and French Opens, while going down in the second round at Wimbledon.
It was Nadal's first Grand Slam defeat after winning the first two sets of a match. The only previous such defeat in his career came in the 2005 Miami finals to Roger Federer.
After a week of punishing heat that saw a record 13 players retire, cooler temperatures returned to Flushing Meadows as top seed Novak Djokovic eased to a third round 6-3, 7-5, 7-5 victory over Italian Andreas Seppi.
It had been a trouble-free visit to New York for Djokovic, the top seeded Serb not dropping a set while losing just 10 games going into his match against Seppi.
But the 25th-ranked Italian at least made Djokovic work for his spot in the round of 16, the world number one needing a tiring two and a half hours to secure his victory.
"Just hanging in there, trying to create my own pace and control the rallies," Djokovic said. "It was a tough three sets."
Frenchman Jeremy Chardy provided the upset of the day dispatching seventh seeded David Ferrer 7-6(6), 4-6, 6-3, 6-1 and the Spaniard was joined at the exit by Canadian 10th seed Milos Raonic who was beaten 6-2, 7-6(4), 6-3 by Spain's Feliciano Lopez.
Venus Williams, who won the second of her two US Open titles 14 years ago, struck a blow for the older set by taming Swiss teen Belinda Bencic 6-3, 6-4.
Venus, 35, produced a vintage power-game performance to beat the 18-year-old in a match-up between the oldest and youngest players left in the women's draw.
Joining the seven-times Grand Slam singles winner in the fourth round was Russian 13th seed Ekaterina Makarova, who advanced with 6-3, 7-5 victory over 17th seed Elina Svitolina of Ukraine.
Men's singles round 3 results:
32-Fabio Fognini (Italy) beat 8-Rafa Nadal (Spain) 3-6 4-6 6-4 6-3 6-4
1-Novak Djokovic (Serbia) beat 25-Andreas Seppi (Italy) 6-3 7-5 7-5
9-Marin Cilic (Croatia) beat Mikhail Kukushkin (Kazakhstan) 6-7(5) 7-6(1) 6-3 6-7(3) 6-1
19-Jo-Wilfried Tsonga (France) beat Sergiy Stakhovsky (Ukraine) 6-3 7-5 6-2
Benoit Paire (France) beat 26-Tommy Robredo (Spain) 7-6(3) 6-1 6-1
27-Jeremy Chardy (France) beat 7-David Ferrer (Spain) 7-6(6) 4-6 6-3 6-1
18-Feliciano Lopez (Spain) beat 10-Milos Raonic (Canada) 6-2 7-6(4) 6-3
23-Roberto Bautista (Spain) beat 14-David Goffin (Belgium) 2-6 5-7 6-3 3-1 (Goffin retired)
Women's singles round 3 results:
1-Serena Williams (U.S.) beat Bethanie Mattek-Sands (U.S.) 3-6 7-5 6-0
Anett Kontaveit (Estonia) beat Madison Brengle (U.S.) 6-2 3-6 6-0
Roberta Vinci (Italy) beat Mariana Duque (Colombia) 6-1 5-7 6-2
23-Venus Williams (U.S.) beat 12-Belinda Bencic (Switzerland) 6-3 6-4
13-Ekaterina Makarova (Russia) beat 17-Elina Svitolina (Ukraine) 6-3 7-5
Kristina Mladenovic (France) beat Darya Kasatkina (Russia) 6-2 6-3
19-Madison Keys (U.S.) beat 15-Agnieszka Radwanska (Poland) 6-3 6-2
25-Eugenie Bouchard (Canada) beat Dominika Cibulkova (Slovakia) 7-6(9) 4-6 6-3