A philosophical Naomi Osaka said on Friday she "is not God" and cannot always win after the defending champion was knocked out of the Australian Open in the third round by unseeded Amanda Anisimova.

The Japanese four-time Grand Slam champion won the first set on Margaret Court Arena but the nerveless American saved two match points in the third to pull off a huge 4-6, 6-3, 7-6 (10/5) upset.

Osaka was making her return to Grand Slam tennis after a long break following a tearful third-round exit at the U.S. Open in September, the culmination of a difficult year where she was plagued by doubt and said she suffered depression.

She said ahead of the Australian Open that her goal for 2022 was to have more fun and she attempted to remain upbeat even after her title defense came to a premature end.

"I fought for every point, I can't be sad about that," the former world number one, who was seeded 13th, said.

"You know, I'm not God. I can't win every match.

"So I just have to take that into account and know that it would be nice to win the tournament, that's really special, and I can't think of myself to try to win the Grand Slam at the start of the year every time.

"I feel like I grew a lot in this match. The last match that I played in New York (U.S. Open) I think I had a completely different attitude, so of course I lost, but I'm happy with how it went."

Defeat to Anisimova deprived the 24-year-old of a shot at world number one Ashleigh Barty in the fourth round. But the new Osaka was relaxed about the missed opportunity.

"To me, it's exciting. Not the loss itself, but the person I lost to because it's showing the growth of tennis," she said.

"I feel like now I'm in this position where if I lose to someone, it might make a headline, but I also think it kind of grows more superstars, and I feel that's good for the game."

Meanwhile, world number two Daniil Medvedev will step up his march towards the Australian Open men's title on Saturday. The U.S. Open champion cemented his status as tournament favorite by overcoming the mercurial Nick Kyrgios in four sets in a raucous second-round encounter on Thursday.

Medvedev, the de facto top seed after Novak Djokovic was deported on the eve of the tournament, now faces a more conventional opponent in Dutch world number 57 Botic van de Zandschulp for a place in the last 16.

But he will not take his opponent lightly in their third-round meeting.

"Grand Slams are tough, there are going to be tough opponents," said Medvedev. "Sometimes you lose early, sometimes you lose late, sometimes you win it. I just want to play really good."