Serena Williams has missed out on winning a record-equalling 24th Grand Slam singles title on home soil this year.
She was beaten 1-6, 6-3, 6-3 in the semi-finals of the U.S. Open by Victoria Azarenka.
The unseeded Belarusian will play Japan's Naomi Osaka in the final on Saturday.
It will be Azarenka's third final at Flushing Meadows, having lost the previous two to Williams in 2012 and 2013.
Fourth seed Osaka had earlier beaten 28th seed Jennifer Brady 7-6, 3-6, 6-3 in the other semi-final.