Serena battled past Tsvetana Pironkova in the quarter-finals.
The 38-year-old will face Victoria Azarenka, who moved into a maiden Grand Slam semi-final since 2013.
In the men's section. Daniil Medvedev reached semis.
Here we present further details.
Medvedev saw off fellow Russian Andrey Rublev in straight sets to progress.
The third seed won 7-6 (8-6) 6-3, 7-6 (7-5) to set up a meeting with second seed Dominic Thiem.
Medvedev, who needed a medical timeout in the final set, is yet to drop a set.
"It was a very tactical game and I am very happy to go through," he said.
Thiem became the first Austrian to reach the semis of the US Open.
"I had a great feeling from the first moment on," said Thiem.
Thiem has been in three Slam finals till date and he would be wanting to get past the distance this time.
Serena had gone down 4-6 in the first set, however, she made a comeback and sealed the next two sets 6-3, 6-2.
Serena grew as the game progressed and broke a tiring Pironkova twice in the third set.
The veteran star is aiming to reach her fifth Slam final since 2017 and a third straight one at the US Open.
Azarenka reached her first Grand Slam semi-final since 2013 with a 6-1, 6-0 win over Belgian 16th seed Elise Mertens.
The two-time Australian Open took advantage of an awful display by Mertens.
Notably, Azarenka broke her opponent six times in total to complete a stunning victory in only 73 minutes.
She had recently won the Western & Southern Open.
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