Azarenka rallied for a 1-6 6-3 6-3 victory on Thursday night in New York for a first major win in 11 attempts against Williams.
Williams took a mid-game medical timeout for an Achilles tendon issue in the second game of the decider and ended up being broken to trail 2-0. Unlike in her three previous rounds, this time there was no comeback for the 38-year-old.
Williams has lost her last four Grand Slam finals as she tried to match Margaret Court’s all-time record of 24, but semifinal defeats in majors are rare. She fell to 33-6.
Azarenka reached her first Grand Slam final since losing the 2013 US Open final to Williams.
She will face Naomi Osaka, who beat first-time Grand Slam semifinalist Jennifer Brady 7-6 (1) 3-6 6-3 in another gripping encounter. Osaka won the crown in 2018 by beating Williams in a controversial finale.
It’s a rematch of the final of the warmup Western & Southern Open, which was also played on the site of the US Open as part of the tournament’s bubble during the coronavirus pandemic.
Osaka, though, withdrew with a hamstring injury to hand Azarenka the title.
Thursday’s matches were played with the roof on at Arthur Ashe Stadium due to rain.