Dayana Yastremska, who opens against Monica Niculescu on Monday, is seeded for the first time at a Grand Slam, the Ukrainian taking the No.32 spot. She is one of nine teenagers taking part this year.
Karolina Pliskova and Ashleigh Barty also begin their campaigns, both with aspirations of taking the No.1 spot from Naomi Osaka.
Kristina Mladenovic has won just one of her five previous meetings with Angelique Kerber, the Frenchwoman winning in Stuttgart two years ago.
Serena Williams is one of 11 former or current World No.1s in this year's draw, while the American is also one of the 15 still-active Grand Slam champions involved this year.
Tenth seed Madison Keys seeks to extend her 4-2 career record over Misaki Doi, although she lost their last meeting, over three sets in Madrid two years ago.
Maria Sharapova is one of eight former US Open champions taking part this year, alongside Kerber, Osaka, Samantha Stosur, Serena, Venus Williams, Sloane Stephens, and Svetlana Kuznetsova.
Five further players have one losing Grand Slam final to their name - Vera Zvonareva, Eugenie Bouchard, Madison Keys, Karolina Pliskova, and Marketa Vondrousova.
Serena Williams remains one Slam short of Margaret Court's all-time Grand Slam record. She is also two behind Molla Bjurstedt Mallory's record of eight all-time US Open titles, and one off Helen Wills Moody.
Sharapova has lost five of her previous 56 Slam first-round matches, while her opponent on Monday, Serena Williams, has lost just one of 72.
Venus Williams draws level with Martina Navratilova on 21 US Open main draw appearances, two ahead of sister Serena. It is the younger sibling who holds the record for most US Open matches (107 ahead of this year) while the 23-time Slam champion could also become the second player to pass 100 US Open match wins (95 before this year). Chris Evert won 101 of her 113 matches here.
Venus Williams is one of 22 players (not including qualifiers) aged 30 or over taking part this week. Someone of that vintage has been a Slam champion 26 times in the Open era.
Warm and sunny, with some cloud. Maximum temperature: 23C/73F
The USA's Nicole Gibbs made it through US Open qualifying, having returned to top-class tennis action following a cancer diagnosis. She tells her story to espnW.
"Venus was never just a player. Her job was never simply to swing a racket and win sets, though that was required. Her job was to change the game." The New York Times' Elizabeth Weil asks if Venus Williams ever got the credit she deserves.
"You never know what to expect." Simona Halep reflects on her US Open experiences so far, talking to wtatennis.com's David Kane.