Novak Djokovic's refusal to be vaccinated against Covid-19 means he again misses out - but there are plenty of storylines to explore.
Here, Planet Sport picks out five things to look out for in New York.
Not even in the most crazy dream could Emma Raducanu have foreseen how the next year would play out when she took her place in qualifying at Flushing Meadows 12 months ago.
The unbelievable high of her first grand slam title has been followed by the inevitable struggles to adjust to life as a full-time tennis player in the full glare of the spotlight.
Raducanu at least goes into the tournament with some good form behind her after victories over Victoria Azarenka and Serena Williams in Cincinnati last week while the US Open balls, derided by Iga Swiatek among others, play to her strengths.
She has a tricky first-round draw against wily Frenchwoman Alize Cornet.
Serena bids farewell
When Serena Williams won her 23rd grand slam singles title at the Australian Open in 2017, it seemed inevitable she would break Margaret Court's all-time record of 24.
But she was hiding a secret, playing in the early stages of pregnancy, and, a month short of her 41st birthday, Williams has decided now is the time to step away.
She could still engineer a remarkable ending, bowing out having finally made it to 24, but, having won only one singles match since the French Open last summer, that appears a pipe dream.
Whenever her tournament ends, one of the all-time great competitors will certainly want to go out swinging.
Serena Williams is set to face Danka Kovinic in Round 1 of the US Open ð¾
She plans to retire after her run at Flushing Meadows pic.twitter.com/ANzOIMIkLn
— Bleacher Report (@BleacherReport) August 25, 2022
Unpredictable women's draws have been a grand slam staple over the last few years - since Williams' last title in 2017, 14 different women have won slam singles titles.
That has been in direct contrast to the men's game, still dominated by the same cohort of aging superstars.
But this tournament could well be different. Rafael Nadal has played just one match since pulling out of Wimbledon with an abdominal injury, world number one Daniil Medvedev has not been in great form and none of the other contenders particularly stand out.
Daniil on the top half, Rafa on the bottom.
The #USOpen men's singles draw is here.
— US Open Tennis (@usopen) August 25, 2022
Norrie looking for more
To have a breakthrough season is one thing, but to follow it up and show you belong at the top of the game is a much harder achievement.
Cameron Norrie deserves boundless praise for his efforts in 2021 and 2022, and the 26-year-old is not finished yet.
Despite gaining no points for his run to the Wimbledon semi-finals - the first time he had made it past the third round at a grand slam - Norrie stands at a career-high nine in the world and is seeded in the top eight at a slam for the first time.
He will be one of the players absolutely believing this can be his tournament.
Raducanu's phenomenal run 12 months ago gave belief to every young player hoping to go big.
In the women's draw, Coco Gauff is already a proven performer at 18 but Dane Clara Tauson and the Chinese triumvirate of Zheng Qinwen, Wang Xiyu and Wang Xinyu could all be names to look out for as well as - if she makes it through qualifying - 17-year-old Czech Linda Noskova.
Carlos Alcaraz of course leads the charge for the men, backed up by 19-year-old Dane Holger Rune and Britain's 20-year-old Jack Draper.
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