British number one Andy Murray will play India's Somdev Devvarman in the first round of the US Open, with Rafael Nadal a potential semi-final opponent.
Fourth seed Murray meets world number 64 Devvarman for the first time.
In the women's singles, fellow Briton Heather Watson has been drawn against former champion Maria Sharapova.
Elena Baltacha will begin against US wild card Jamie Hampton and Anne Keothavong plays South Africa's Chanelle Scheepers.
"It could have been a worse draw for sure but I don't ever want to take anyone for granted," said British number one Baltacha, who beat Hampton over three sets at the Australian Open in January.
"This is her home Grand Slam so she's going to play well. I had a tough match against her in Australia so I know she has the potential to be dangerous and she's a fighter.
"My preparation has been great though, so I'm going in feeling pretty confident about my game."
The final Grand Slam tournament of the year gets under way in New York on Monday, and Thursday's draw took place at the Arthur Ashe Stadium at Flushing Meadows.
World number one Novak Djokovic could face a repeat of last year's semi-final against Roger Federer, which the Serb won before losing to Rafael Nadal in the final.
Djokovic begins his campaign for a first US Open title against a qualifier, while Nadal plays Andrey Golubev and five-time champion Federer takes on Santiago Giraldo.
Murray will hope to improve on third and fourth-round exits in the last two years and arrives on the back of winning the Masters titles in Cincinnati.
Devvarman, 26, is the current Commonwealth Games champion and hit a career-high of 62 in the world last month.
Serena Williams might be seeded down at 28 as she continues her comeback from injury, but two tournament wins in recent weeks have made her a strong favourite at Flushing Meadows.
The American plays 19-year-old Serbian Bojana Jovanovski, ranked 52nd, in round one and could face fourth seed Victoria Azarenka as early as the third round.
Venus Williams, who is unseeded, meets Russia's Vesna Dolonts in round one and could play Wimbledon semi-finalist Sabine Lisicki in the second round.
Top seed Caroline Wozniacki will first meet Spain's Nuria Llagostera Vives and second seed Vera Zvonareva faces a qualifier.