For two hours and 30 minutes, Azarenka and Williams engaged in a seesaw centre court battle before the second ranked Belarusian finally clinched the victory, winning a nervy tiebreak 8-6 to stop the American from ticking one 'to do' item off her 'bucket list'.
In a career that has generated 54 singles titles, including 16 grand slams, Williams had won just about everything there is to win in her sport - but not Cincinnati, one of the WTA Tour's most prestigious tournaments.
Cincinnati will remain a hole on her resume for at least another year after Azarenka answered the challenge claiming just her third win in 15 tries against the 31-year-old American.
Williams came into the contest with a chance to reach several career milestones beyond a first Cincinnati win but failed to reach any of them.
It was only the second time in 10 finals this season that Williams had failed to walk away with the trophy and with a victory on Sunday would have moved up a notch on the career wins list into a tie for seventh place with Britain's Virginia Wade and compatriot Lindsay Davenport.
But the day belonged to Azarenka, who bagged her third title of the year and 17th of her career.
A marquee final featuring the world's number one and two ranked players initially failed to deliver the high-quality spectacle expected from the two women who have captured five of the last seven grand slams.
Azarenka, who struggled with her serve against Jelena Jankovic in the semi-finals holding just three-times, opened the match with two double faults to hand Williams the early break.
Williams would continue her assault on Azarenka with another break at 4-1 that left the Belarusian waving her racket in anger.
But in the second set it was Azarenka who had Williams talking to herself as she turned the tables on the muscular American breaking her three times to level the match.
In the third, Azarenka and Williams finally produced the tennis and edge-of-your-seat drama that fans had come to see twice trading breaks to send the set to tiebreak.
With the title on the line, the quality of shots and effort sky-rocketed at both ends of the court before the contest ended with Williams' forehand into the net.
