They have combined to win each of this year's previous three majors - Federer also won Wimbledon while Nadal was victorious in the French Open.
For Sharapova, a former world number one and five-times grand slam champion who returned from a 15-month doping ban in April and was awarded a wild-card invitation to the U.S. Open, it will mark her first match since pulling out of the Stanford Classic three weeks ago with an arm injury.
Federer and Nadal have never met at Flushing Meadows.
Sharapova faces a hard test Monday in the night feature match at Arthur Ashe Stadium against world number two Simona Halep of Romania. Nadal won the French Open this year. British number one Johanna Konta will begin her campaign against Aleksandra Krunic of Serbia, who is ranked 77 in the world.
Eight women enter with a shot at being ranked No. 1 when the U.S. Open ends: Karolina Pliskova, the 2016 runner-up who now holds the top spot, Halep, Muguruza, Elina Svitolina, Caroline Wozniacki, Johanna Konta, Svetlana Kuznetsova and Venus Williams.
On the women's side, Pliskova is the top seed in action and she will face Magda Linette on Tuesday.
Defending champion Kerber is priced up around the 16/1, but those odds are a reflection of a season in which she has failed to reach the last eight of any Grand Slam event.
Federer is undoubtedly one of the great champions at Flushing Meadows, having won the title five straight years between 2004 and 2008.
If Federer and Rafael Nadal were to make it through to the semi-finals it would be their first ever meeting at the US Open.
Andy Murray has been absent from the tour with a hip injury since Wimbledon. The world no six is in Murray's half of the draw and will be playing well into the second week.
Australian Nick Kyrgios, the 14th seed and recent Cincinnati runner-up, or American 17th seed Sam Querrey, who is enjoying a career-best year, would pose a threat to Federer in the fourth round.
Federer also beat Nadal in the final of the Miami Open to complete the "Sunshine Double" in March.
Third seed and 19-time Grand Slam victor, Roger Federer has been confirmed into the same half of the draw as World No.1Rafael Nadal at the US Open which starts on Monday (NZT) in NY.
Unfortunately, one of the big story lines entering the tournament is who isn't playing.
USA 10th seed John Isner, the top-ranked player in his quarter of the draw thanks to a reshuffling when Britain's Andy Murray withdrew due to a hip injury, opens against France's Pierre-Hugues Herbert.
When No. 2 seed Murray pulled out Saturday, there was hope that Federer would get slotted into the other half of the draw - to set p a potentialFederer vs Nadal final. Nadal has lost in the first round of a grand slam once since 2014.
If you're looking for an American man to do well, stick with John Isner.
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