The 33-year-old American, with the 2015 Australian Open, French Open and Wimbledon trophies already on her crowded mantle, will be gunning to complete the first season's sweep of the slams since Steffi Graf in 1988.
The last man to accomplish the feat was Rod Laver in 1969.
"I am sending her good vibes, I hope she does it," says U.S. Open men's top seed Novak Djokovic, winner of nine majors.
"She’s a true champion and she’s impressive what she’s managed to do so far at her age to win three grand slams. It’s
quite incredible. I know how tough it is, both men’s and women’s tennis. The competition is really high."
Victory at Flushing Meadows would lift Williams to 22 career grand slam singles crowns, tying her with Graf for second on the all-time list, two behind Margaret Court.
"I hope she does it, number one," said second seed Roger Federer, who stands atop the men's all-time slams list with 17.
"Number two, of course it’s intriguing and interesting to see. You don’t get this kind of an opportunity many times in tennis, so it will be very interesting to follow."
Rafa Nadal, a 14-times grand slam singles winner, was also absorbed by the historical bid by Williams, who has won the last three titles at Flushing Meadows and would register an Open era record seventh U.S. crown with another triumph.
"She won everything that somebody can win. Amazing the career of Serena," said Nadal. "She has a unique opportunity to make the Grand Slam in one year and she's playing at home so it's a big opportunity for her.
"She knows how to manage all of this. She knows how to play in this tournament. She has won here many times."
Williams would become the sixth player to register a Grand Slam following Don Budge (1938) and Laver (1962, 1969) on the men's side and Maureen Connolly (1953), Court (1970) and Graf (1988).
"If she makes that happen it will be something special for the world of sport," Spain's Nadal said.
All three of these leading men have come close to the feat.
Federer won three of the four slams in 2004, 2006 and 2007, falling short all three years in the French Open, losing in the '06 and '07 finals to nine-times Roland Garros winner Nadal.
Nadal won three in 2010, missing only the Australian Open, while Djokovic won a trio in 2011, lacking the French title.
None of them came to Flushing Meadows with a chance to complete the slam.
Djokovic was asked if he thought he might be capable of a Grand Slam.
"I sincerely hope from your mouth to God’s ears," the 28-year-old Serb said. "I’ve been close and that gives me enough reason to believe that I can achieve that."
(Editing by Andrew Both)
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