Big-hitter Khachanov eased through the match without dropping a service game to eighth seed Wawrinka.
The 36-year-old Frenchman wrote on Twitter on Friday that mental health is also a concern.
The 20-time Grand Slam champion was due to be playing in Rotterdam for the first time since 2009.
"For sure he has more experience, but more things to lose," Medvedev said about his final opponent Novak Djokovic.
Medvedev proved far too strong for Tsitsipas, crushing him 6-4, 6-2, 7-5 in front of more than 7,000 noisy fans at Rod Laver Arena to extend his win streak to 20.
Australian Open 2021 Highlights: Daniil Medvedev beats Stefanos Tsitsipas, faces Novak Djokovic in the final
Australian Open 2021 Semi finals: Daniil Medvedev beat Stefanos Tsitsipas 6-4, 6-2, 7-5 in the men's semi-final. He faces eight-time Australian Open champion Novak Djokovic in the final on Sunday.
After beating qualifier Aslan Karatsev, Djokovic, showing no ill-effects from an abdomen injury sustained in the third round, said, "This is the best I've felt in the entire tournament. I could swing through the ball. No pain. The best match so far."
"I wasn't thinking about a lot of things," said Tsitsipas. "How would I describe myself? Nirvana. Just was there... playing, not thinking."
"I'm not the guy that's going to find excuses on that or going to complain about what happened, no. Just accept. I never considered myself an unlucky person at all," Rafael Nadal said after his ouster.
Karolina Muchova's only other victory over a top-five was against No 3 Karolina Pliskova at Wimbledon in 2019.
Greek tennis player Michail Pervolarakis tests positive for COVID-19 days after playing ATP Cup in Melbourne
Pervolarakis, who played singles and doubles for Greece at the team event, said he tested positive on arrival in South Africa.
The pair were born within weeks of each other and often pitted together as juniors, but Greek fifth seed Tsitsipas swatted the Swede 6-4, 6-1, 6-1 on John Cain Arena.
Australian Open 2021: Fans empty stadiums once again but not before highlighting they're essential to tennis
Beyond the record attendances, the finances of the tournaments, it is real people spurring real athletes on to places they wouldn't think existed.
Australian Open 2021: Daniil Medvedev finally wins five setter, frustrated Karolina Pliskova knocked out
The win stretched Medvedev's winning streak to 17 matches, including his successful run to the title at the 2020 season-ending ATP Finals.
Australian Open 2021: Sofia Kenin's title defence ends early; Rafael Nadal, Stefanos Tsitsipas through to third round
Delivering 10 aces, Kanepi powered her way past the No. 4-seeded Kenin, overwhelming the 2020 champion 6-3, 6-2 in just 64 minutes
Tsitsipas has a lot of support within Melbourne's large Greek community and felt at home in an extended on-court interview.
Djokovic pointed to Greece's Tsitsipas, Germany's Zverev, Canada's Denis Shapovalov and Italy's Matteo Berrettini as capable of breaking through
Slimmed down ATP Cup 2021 gets underway on Tuesday with smaller field of 12 nations and a lighter prize cheque.
The giant Russian, 24, has now won 10 consecutive matches following his title earlier this month at the Paris Masters and his victory will taste sweet a year after a winless debut in London
ATP Finals 2020: Nadal earns hard-fought win over Tsitsipas to reach semi-finals; Rublev downs Thiem in dead-rubber
Nadal, whose haul of 86 singles titles includes just one on indoor hard courts, is chasing the biggest prize missing from his resume at the eight-man elite event.