In February 2021, Karatsev went through qualifiers for the Australian Open. In his first main draw of a Grand Slam, ranked 114th, he defeated 8th seed Diego Schwartzman, 20th seed Félix Auger-Aliassime and 18th seed Grigor Dimitrov to reach the semifinals. Karatsev is the first man in the Open Era to reach the semifinals in his Grand Slam debut.[2]