As only Kyrgios can do, the Aussie went on to win that service game, despite his underarm serve, and went on to force the match in the a third set tiebreak as the match ticked over the three hour mark.
Isner served 19 aces in a 6-4 6-4 win over Sam Querrey and Millman was untroubled by Peter Gojowczyk, easing to a 6-0 6-2 victory. Kyrgios, in contrast, looked weary, exhausted from the outset and far from being in form.
During the second set, he tried to trick Nadal by serving an underarm shot, which went wide.
The post-match handshake between the two players was also a little tense and Nadal didn't hold back in his criticism after the match.
He could win grand slams and fight for the top positions of the ranking, but there is a reason why he is where he is.
"What has happened in the last five minutes of the game has been a reflection of what happened in the second and third sets", Nadal explained. "I love going out there and playing big matches".
The match consisted of a few theatrics from Kyrgios, which sparked boos from the crowd from the onset and throughout.
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Williams' alleged attacker, 28-year-old Zachary Greenberg, was arrested Friday but is now out on bail. Both sides said they were open to further talks, though a third summit has not been scheduled.
Nadal won the first set comfortably, before Kyrgios complained that he was feeling sick and called for his trainer. "The media's gonna blow it up".
He returned to the court for the second set and immediately looked a different player. Nadal had also expressed annoyance with the spectators' noise. Kenin led 6-4, 4-1 when Katie Boulter retired.
Kyrgios, ranked 72 in the world, hit back at Nadal.
Kyrgios said he still considers Nadal one of the best players of all time.
The 31-year-old former world number one has already said she would not play in the March 6-17 BNP Paribas Open at Indian Wells, California.
Despite having been booed and struggling throughout the match, and despite having poor overall stats in the match, it was Kyrgios who emerged on top. Serving to stay in the match, Mischa got broken for the third time when Rafa places a flawless backhand down the line victor to reach the second round where he will face Nick Kyrgios.
"He lacks respect for the public, the opponent and toward himself", added Nadal, who said he did not think Kyrgios was a "bad guy".