As she seeks the first Grand Slam since 1988, the top-ranked Williams might find herself competing against the past and future of her country's championship hopes.
A potential third-round opponent is 22-year-old Sloane Stephens, who beat her in the 2013 Australian Open quarterfinals and is coming off her first WTA title in Washington this month. A possible fourth-round foe is 20-year-old Madison Keys, who reached this year's Aussie semifinals.
Then in the quarterfinals, she could face her sister, seven-time Grand Slam winner Venus Williams. Serena had to beat Venus in the fourth round at Wimbledon on the way to her second "Serena Slam" - four major championships in a row, but just not in the same year.
Now Williams is attempting to complete the first Grand Slam since Steffi Graf 27 years ago.
Asked about the potential matchup with her sister after Thursday's draw ceremony, Williams laughed and said: "It's better than the round of 16, so that's how I look at it."
Another potential quarterfinal opponent is 12th-seeded Swiss teen Belinda Bencic, who recently upset Williams in Toronto en route to a breakthrough title. Williams could face Maria Sharapova for the second straight major semifinal after beating her Russian rival for the 17th consecutive time at Wimbledon.
There are nine U.S. players in all in Williams' quarter of the bracket. Based on recent results, facing the young Americans early in the tournament could help keep Williams sharp under the pressure of her Grand Slam pursuit.
Since the upset by Stephens in early 2013, Williams has lost just once to a countrywoman - to Venus more than a year ago. Of course, she hasn't lost much to anyone during that span.
She avenged the loss to Stephens with a straight-set victory in the 2013 U.S. Open then defeated her three more times this year, including a come-from-behind win in the fourth round at the French Open. And Williams won her only meeting with Keys in that Australian Open semifinal.
"You have Sloane, I seem to play her every tournament," Williams said. "Madison is playing really well. So is Sloane, actually - she's playing excellent. So it's not anything simple or easy to go through."
Williams' first-round opponent is 86th-ranked Vitalia Diatchenko of Russia, who she has never played. A potentially tricky second-round foe is Mirjana Lucic-Baroni, who made a resurgent run to the fourth round of last year's U.S. Open.
Second-seeded Simona Halep and fourth-seeded Caroline Wozniacki, who lost to Williams in the 2014 U.S. Open final, are in the other half of the draw.
On the men's side, second-seeded Roger Federer and No. 3 Andy Murray could meet in one semifinal, with No. 1 Novak Djokovic and No. 4 Kei Nishikori, last year's runner-up, in the other.
Djokovic could face Rafael Nadal, who's seeded just eighth, in the quarterfinals. Nadal has a tough first-round match against fast-rising 18-year-old Borna Coric of Croatia, who just missed out on a seed with a ranking of 35th in the world and last year won their only head-to-head meeting.
Murray has an intriguing opening match with another young player who just missed out on a seed, 37th-ranked Nick Kyrgios.
The 20-year-old Australian comes into the U.S. Open with controversy swirling around him, facing a provisional suspension from the ATP for comments made to Stan Wawrinka in Montreal. During their match Aug. 12, a courtside microphone picked up Kyrgios saying that fellow Australian Thanasi Kokkinakis had slept with a player who reportedly is now Wawrinka's girlfriend.
Kyrgios has given Murray little trouble on the court, losing in straight sets in this year's Australian and French Opens.
Nishikori could face defending champ Marin Cilic, who's seeded ninth, in the quarters in a rematch of last year's final.
