The Japanese won 1-6 6-3 6-3 inside Arthur Ashe Stadium, becoming only the fifth player in the Open Era to win her first three finals at the Majors.
It was a staggering effort, not least because she lost the first set in little more than 27 minutes, with Azarenka carrying on where she left off against Serena Williams in the semi-finals.
At that stage, the final at Flushing Meadows looked set to be disappointingly one-sided and brief, and that sense was only accentuated when Azarenka broke immediately in the second set, too.
By then there had already been one racket fling from Osaka, the 22-year-old who might just become the dominant player of her generation but found herself in a huff.
Suddenly, however, the match flipped. Osaka began to land her big shots, and the result was that she won seven of the next eight games.
Azarenka, a two-time Australian Open champion, lost back-to-back US Open finals to Williams in 2012 and 2013, and she dearly did not want to experience that feeling again.
When Osaka broke to lead 3-1 in the decider, it seemed Azarenka was destined to experience that unwanted hat-trick.
It came as a surprise when Osaka then allowed Azarenka three break points in the next game, but somehow she avoided dropping serve.
In a match of twists, there were more to come, firstly with Azarenka scoring that much-needed break back in Osaka's next service game, only to then lose her own serve.
Osaka, 5-3 up, serving for the match, just about held her nerve as Azarenka kept the pressure on.
Eventually, Azarenka netted a backhand, and Osaka shrieked in delight, touched rackets with Azarenka and lay down on the court.
She had every right to savour the moment. Champion in 2018, that night was overshadowed for many, even perhaps for Osaka, by Williams, on her way to defeat, rowing with chair umpire Carlos Ramos.
This time it was Osaka's moment and hers alone. A wide smile across her face told its own story.