Japanese fourth seed Osaka, 22, won 1-6 6-3 6-3 for her second US Open title.
Osaka was overwhelmed in the first set and was in danger of trailing 3-0 in the second before recovering to win 10 of the next 11 games to take momentum.
Belarusian Azarenka, playing in her first major final since 2013, lost serve for 5-3 in the decider.
Osaka shrieked with joy as she took her second match point, then calmly laid out on the court and stared at the New York sky as she contemplated her latest achievement.
Osaka’s level raised considerably as 31-year-old Azarenka was unable to maintain the intensity she showed in a one-sided opening set.
The fightback ensured Osaka, who won the 2018 US Open and 2019 Australian Open, maintained her record of winning every Grand Slam final she has played in.
“I don’t want to play you in any more finals, I didn’t really enjoy that, it was a really tough match for me,” Osaka jokingly told Azarenka.
“It was really inspiring for me because I used to watch you play here when I was younger. I learned a lot, so thank you.”