While the year's final Grand Slam has been stripped of some of the marquee names, with Roger Federer, Rafa Nadal and Serena Williams injured, it is still shaping up as an absorbing event in Flushing Meadows as Novak Djokovic bids to complete the calendar-year slam.
Already the winner of the Australian and French Opens and Wimbledon, the Serb needs a New York triumph to become the third man, and first since Rod Laver in 1969, to accomplish the feat.
The history hunting Djokovic opens his account on Wednesday with a first round match against Danish qualifier Holger Rune.
Third seed Osaka will be the headliner on Day One when she launches the defence of her U.S. Open crown against the Czech Republic's Marie Bouzkova.
It will mark the 23-year-old's first appearance in a Grand Slam since dropping out of French Open in June and skipping Wimbledon to deal with mental health issues.
The contest is sure to pull in a crowd at Arthur Ashe Stadium with fans, who must show proof of vaccination to enter the grounds, filling seats in the massive venue after a COVID-19 pandemic forced last year's event to unfold in eerie emptiness.
"It's certainly nice to be back here now," said Australia's women's top seed Ash Barty.
"This week is going to be exciting. It's got fans. That's going to bring a lot of energy to this tournament.
"This is a tournament that thrives with the energy."
Opening day will see two of the big threats to Djokovic's shot at history, with second-seeded Russian Daniil Medvedev and Greek third seed Stefanos Tsitsipas both in action.
Medvedev, finalist at Flushing Meadows in 2019, takes on Frenchman Richard Gasquet, while French Open finalist Tsitsipas faces 2012 U.S. Open champion Briton Andy Murray.
Centre court action kicks off with an all-American rematch of the 2017 women's final featuring Madison Keys and winner Sloane Stephens.
A long day's play will end with the possibility of some late-night fireworks with unpredictable Australian Nick Kyrgios taking on Spain's 18th seed Roberto Bautista Agut in the last match at Louis Armstrong Stadium.
New Zealanders Michael Venus and Marcus Daniel are both in the men's doubles draw.