Aiming to be the first man in the Open era to win his second major title on his next Grand Slam appearance, Medvedev had a 6-1, 6-4, 7-6 (3) win over Henri Laaksonen on Tuesday in the first round at Melbourne Park.
Defending champion Djokovic was already back in Serbia, two days after losing his legal challenge to stay in Australia despite being unvaccinated against COVID-19, when Medvedev went onto Rod Laver Arena and raced through the first set in 26 minutes.
Nobody has dominated on that court like Djokovic, who was unbeaten in the nine finals he reached at the Australian Open. Medvedev was the most recent recipient of one of those beatings, losing last year's championship match.
But he avenged that with his breakthrough major title at the US Open, where his victory meant Djokovic's bid for a calendar-year Grand Slam finished one win short.
"I'm feeling great ... hopefully I can show some good signs here throughout the two weeks,'' Medvedev said. "I like pressure.
"Always want to do better than I did last year, [but] it's not going to be easy."
This was the first match of 2022 for Kyrgios, who pulled out of a tuneup tournament in Sydney on Jan. 10 after testing positive for COVID-19. He said his bout of COVID-19 "hit me pretty hard.''
"Anyone that's been through it, I hope honestly for the best. Obviously physically I don't feel 100 percent, but I'm not going to use that as an excuse,'' he said. "Like, everyone is dealing with that at the moment. The whole world is dealing with it. So I'm just going to take it day by day.''
Five-time finalist Andy Murray needed a tough five-setter over a player he beat last week to register his first win in an Australian Open match since 2017.
Murray, playing thanks to a wild-card invitation, beat 21st-seeded Nikoloz Basilashvili 6-1, 3-6, 6-4, 6-7 (5), 6-4 to move into the second round.
Murray also fended off Basilashvili last week on the way to the final in a Sydney tuneup event.
It was Murray's 49th win in an Australian Open singles match, moving him ahead of Andre Agassi and Ivan Lendl into fifth-place all time. According to the International Tennis Federation, it's the most match wins at a Grand Slam tournament without winning the title, surpassing Lendl's 48 at Wimbledon.
Regardless, match win No. 50 in Australia is the immediate priority. He next plays Taro Daniel, a qualifier from Japan.
Murray's wasn't the only dramatic five-setter that finished in the early evening on Day 2.
Ninth-seeded Felix Auger-Aliassime fended off Emil Ruusuvuori 6-4, 0-6, 3-6, 6-3, 6-4, and Maxime Cressy overcame 20 double-faults to upset fellow American and No. 22-seeded John Isner 7-6 (2), 7-5, 6-7 (4), 6-7 (4), 6-4.
Earlier in the men's draw, No. 5 Andrey Rublev beat Gianluca Mager 6-3, 6-2, 6-2, No. 11 Jannik Sinner beat Joao Sousa 6-4, 7-5, 6-1, No. 13 Diego Schwartzman beat Filip Krajinovic 6-3, 6-4, 7-5 to advance along with No. 15 Roberto Bautista Agut and No. 27 Marin Cilic.
Eighth-seeded Casper Ruud was forced to withdraw from his first-round match because of an ankle injury. The Norwegian player was in the same quarter of the draw as Stefanos Tsitsipas. Ruud twisted his ankle in practice two days before the tournament began.
"I hoped that I would be able to recover and be able to step on court today with the two days that I had, but rolling an ankle usually maybe needs some more time," Ruud said. "I tried everything I could to be ready, but unfortunately I've decided that I'm not ready.''
He was replaced in the draw by Roman Safiullin, a lucky loser from qualifying who will now face Slovakian Alex Molcan in the opening round.
Fourth seed Tsitsipas wrapped up the men's program at Rod Laver Arena with a 6-2, 6-4, 6-3 win over Mikael Ymer.
Tsitsipas, a runner-up at the French Open and a semifinalist in Australia last year, will play Sebastian Baez in the next round.
The Associated Press contributed to this report.