Next up for Keys, who was routed by Sloane Stephens in last year's final, is the victor of the evening clash between five-times Grand Slam champion Maria Sharapova and Spanish 30th seed Carla Suarez Navarro.
Should Federer get through against the 55th-ranked Australian, he'll set up his earliest Grand Slam meeting with Djokovic since 2007, when Federer beat Djokovic to reach the Australian Open quarter-finals.
"I'm probably in a little bit of disbelief", Millman said after smashing Federer's 40-from-40 record against non-top 50-ranked rivals at the US Open.
WHAT IT MEANS: We're one step closer to a much-anticipated Djokovic-Roger Federer quarterfinal, which would be their 47 meeting on the ATP World Tour (Djokovic holds a slight 24-22 advantage) and their seventh at the US Open.
That proved to be all Federer needed as he clinched the first set.
Millman, ranked 55, could not be less like his compatriot Kyrgios.
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Their first ever meeting at the Madrid Masters in 2015 had all three sets go into tie-breakers to give Kyrgios his only win. Lahyani stood over the seated Kyrgios, berating the 23-year-old. "Just call the trainer to the court and I'll try ".
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A Federer v Djokovic clash would provide the flawless contest to propel the US Open into the second week, with the two champions having claimed seven titles at Flushing Meadows between them.
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. Federer served 10 double faults and committed a frankly staggering 76 unforced errors throughout the match, which helped pave the way for easily the biggest win of Millman's career.
Kei Nishikori, runner-up in 2014, was also pleased to get through in three sets in blazing sunshine on Louis Armstrong Stadium. Roger had it on a string, he was manipulating me around the court.
Federer punished him by snatching a break of his own but his own struggles returned as he looked to serve out the set.
Federer hit back midway through the fourth, breaking Millman to 15 to offer himself a lifeline in the match.
Federer wasted two set points in the 10th game, giving Millman a break chance when he missed an easy volley then double-faulting on break point.