Fight back
The momentum from winning the set kept Kyrgios from spiralling mentally, but he became sloppy in the second, committing four double faults with only three aces, and he had 12 unforced errors with seven winners. It was the only set he had more than one double fault and more unforced errors than winners.
Medvedev's ability to return in the second set was the difference, lifting his return point success rate from 33 per cent in the opener to 48 per cent to break twice and even up the match.
Kyrgios meltdown
It had all the makings of a Kyrgios meltdown, but where he would usually begin to unravel and force desperate power shots to shorten points, he instead settled into the battle and refocused on getting into the net.
After only going to the net five times in the second set, he tripled that in the third, winning nine-of-15 attempts while not allowing a single break point opportunity. Kyrgios only created one break point chance for himself, and he took it with both hands to go up two sets to one.
Khachanov next
In the fourth, Kyrgios was able to break again with his first opportunity early on, and with his serve switched on and firing he would only allow one chance for Medvedev to break back, but he snuffed it out before going on to secure a second break and the victory.
Of their five career meetings, Kyrgios has now won four, and he will now get the benefit of the No.1 seed's path through the tournament. Next up, he will face 27th seed Karen Khachanov in the quarterfinal as he searches for his first career Grand Slam title.
Medvedev loses No.1 ranking
For the records, Kyrgios is the first player since 1987 to defeat the world No.1 twice in the same year, with Australian compatriot Pat Cash the last to do it. It is also the first time an Australian has defeated a world No.1 in a Grand Slam since Kyrgios himself, back in 2014 as a 19-year-old against Rafael Nadal at Wimbledon.
Medvedev will lose his top spot in the ATP rankings after the US Open. Rafael Nadal, Carlos Alcaraz or Casper Ruud will become the new world No.1.