The 32-year-old Williams has won 17 Grand Slam titles. At age 18, Taylor Townsend is in her third major tournament.
Townsend is a former top-ranked junior player who reached the third round at the French Open this year. She got into her first U.S. Open main draw with a wild card.
On the men's side, Wimbledon champ Novak Djokovic and Australian Open champ Stan Wawrinka could meet in one semifinal. Second-seeded Roger Federer and fourth-seeded David Ferrer are in the other half.
Williams, seeking her third straight title at Flushing Meadows, hasn't reached the quarterfinals at any of the first three Grand Slam events of 2014.
"The way my year's been going, I'm worried about every single match," she said after Thursday's draw ceremony.
If she makes the quarterfinals, she could meet eighth-seeded Ana Ivanovic, who beat her at the Australian Open. Wimbledon champ Petra Kvitova could await in the semifinals.
Seventh seed Eugenie Bouchard of Westmount, Que., opens against Olga Govortsova of Belarus. Bouchard has advanced to at least the semifinals of the other three Grand Slams this year but has struggled so far on hardcourt.
Kvitova and Bouchard could play a rematch of their Wimbledon final in the quarter-finals.
Kvitova, though, has always struggled at the year's last major tournament, never even reaching the quarters. After she won her first Wimbledon title in 2011, she lost in the first round at the U.S. Open.
Kvitova could face two-time Australian Open champ Victoria Azarenka in the round of 16. Azarenka lost to Williams in the finals at Flushing Meadows the last two years but is seeded just 16th after an injury-plagued season.
Second-seeded Simona Halep and fourth-seeded Agnieszka Radwanska are in the other half of the draw. Halep could meet five-time major champ Maria Sharapova in the quarterfinals.
Sharapova, seeded fifth, has a tough first-round matchup against fellow Russian Maria Kirilenko, who has been ranked as high as 10th and is a three-time major quarter-finalist.
Seven-time major champ Venus Williams could face Halep in the round of 16, though Williams hasn't gotten that far at a major tournament since 2011. The 34-year-old Williams, seeded 19th, meets 43-year-old Kimiko Date-Krumm in the first round.
Serena Williams could play 2010 French Open champion Francesca Schiavone in the second round. At age 34, Schiavone is down to 76th in the rankings, and in the first round in New York last year she lost 6-0, 6-1 to Williams.
Aleksandra Wozniak of Blainville, Que., opens against Japan's Nara Kurumi, while Toronto's Sharon Fichman faces Radwanska.
Djokovic could face Andy Murray in the quarterfinals. Murray beat Djokovic for both his major titles but has struggled some this year after back surgery and is seeded eighth.
In the round of 16, Murray could get ninth-seeded Jo-Wilfried Tsonga, who beat Djokovic, Murray, Grigor Dimitrov and Federer to win the title at the hard-court tournament in Toronto this month.
Wawrinka could meet Wimbledon semifinalist Milos Raonic of Thornhill, Ont., in the quarter-finals. The seventh-seeded Dimitrov, the other young player to break through with a semifinal run at Wimbledon, could face Federer in the quarters.
Raonic, the fifth seed, will face a qualifier in the first round. Vancouver's Vasek Pospisil faces Italy's Simone Bolelli and Frank Dancevic of Niagara Falls, Ont., meets No. 32 Joao Sousa of Portugal.