Roger Federer lost to a player ranked outside of the top 50 for the first time at the US Open as Australia's John Millman stunned him to set up a quarter-final against Novak Djokovic. Nishikori advanced in the afternoon with a 6-3, 6-2, 7-5 victory over Philipp Kohlschreiber.
It's only the second time in Federer's past 14 appearances at the US Open that he has lost before the quarterfinals.
Millman fought back from being down a break early in the fourth set to force a tiebreak.
Federer, indeed, did not play as well as he had in the opening three matches, when he didn't drop a set. The Australian then seemed to be in trouble as the five-time champion broke him for a second time in the match in game five and then served for the set at 5-4.
Asked Monday whether he thought during that time away about returning to the height of his powers, Djokovic replied: "I have imagined".
Before their match, Roger Federer said he had a great deal of respect for his Australian counterpart.
Sousa, who got past 12th-seeded Pablo Carreno Busta and No. 17 Luca Pouille to become the first Portugese man to reach a Grand Slam last 16, was irked by the chair umpire's refusal to allow a line call challenge in the seventh game of the final set.
But on the very same court on which Federer destroyed Hewitt 6-0 7-6 6-0 in the 2004 US Open final, Millman stared down the greatest player of the professional era to send the world No.2 crashing to his earliest grand slam defeat in nearly four years.
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Madison Keys returned to the U.S. Open quarterfinals with a 6-1, 6-3 victory over No. 29 seed Dominika Cibulkova of Slovakia.
'One of the big things with the top players at the moment, we're looking at these guys and saying well how come they're playing so good deep into their 30s? In fact, he has never won an ATP event, falling in the final to Marco Cecchinato of the Hungarian Open earlier in April, according to a report on the website of US Open.
In the women's draw, Maria Sharapova was delivered a surprising upset at the hands of Spain's Carla Suárez Navarro.
'I felt like a bit of a deer in the headlights to begin with, my feet weren't moving.
Both Nishikori and Djokovic missed last year's U.S. Open with arm injuries.
Kei Nishikori will be hoping to make another deep run at his most successful grand slam event after he outclassed Philipp Kohlschreiber 6-3 6-2 7-5 to reach the quarter-finals of the US Open on another scorchingly hot day in NY.
She was able to play through the pain and eventually won the match in 2 hours, 32 minutes.