The favorite would complete a historic grand slam for 2021 and secure a 21st major title by winning against second-seed Daniil Medvedev.
The Serbian defeated the Russian in the final in Melbourne, before triumphing at Roland Garros and Wimbledon.
Djokovic is trying to become the first player to win all major tournaments in a single year since 1969, when Rod Laver did.
Djokovic, Roger Federer and Rafael Nadal are tied with 20 major tournament titles each.
The 34-year-old Djokovic is 3-5 in the final in New York.
Medvedev, 25, is trying to win a first grand slam title.
He reached the final at Flushing Meadows in 2019, where he lost to Nadal.
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