Twelve months after losing the final to Naomi Osaka, Williams will have to hit the ground running in her quest for a 24th Grand Slam title.
Federer, owner of a record 20 Grand Slam titles, considers himself in fine form despite a forgettable U.S. Open tune-up that consisted of a swift third-round upset in Cincinnati.
33 - Williams, like Federer in the men's tournament, is aiming to become the oldest women's US Open champion of the Open Era at 37.
"I just come here to play and do the best that I can", Barty said. And as a tennis player, I could not have that.
The biggest question surrounding the 19-year-old Canadian Andreescu is her health as she has battled back, leg and shoulder issues.
French Open champion Ash Barty or Wimbledon victor Simona Halep, who ran Williams off the court in a lopsided final at the All England Club, may be sounder investments at the betting window but punters are just as likely to follow their hearts as hunches.
While it's Osaka's first time defending a Slam, she had her first taste of defending a title this year at Indian Wells.
In an interview to The New York Post, the 18-time Grand Slam victor Chris Evert commented on Serena Williams's chances to equal Margaret Court's 24 Majors at the US Open.
"Arrive to the big events with good feelings helps", Nadal said. That's kind of how I've been in my whole career.
Spanish second seed Rafael Nadal opens the night session against Australian John Millman, who upset Federer in last year's first round, with 2017 US Open victor Sloane Stephens, the US 11th seed, facing Russia's Anna Kalinskaya. "I'm very much aware of how I need to approach this tournament mentally".
Second-ranked Nadal, an 18-time Grand Slam victor who took his 12th French Open title in June, isn't too excited over Federer and Djokovic both being in the opposite half of the draw. They met in a classic final at Wimbledon, where Djokovic won in a fifth-set tie-breaker. I know how it works.
Russia's Daniil Medvedev has enjoyed a stellar US Open run-up with a win at Cincinnati and runner-up efforts at Washington and Montreal.
As for Britain's Johanna Konta, the Sydney-born player appears to have completely lost confidence since suffering a shock quarter-final defeat at Wimbledon to doubles-specialist Barbora Strycova of the Czech Republic. "Over time I guess you get more used to it".
Austrian fourth seed Dominic Thiem meets Italy's Thomas Fabbiano in the next match. "There are some times I definitely think to myself I'm really blessed to be in this position and then there is bad things that come with that".
A hard few months saw her fail to win a tournament, lose her number one ranking and crash out of Wimbledon in the first round.