Three-time defending champion Williams launches her bid for more tennis history Monday at Arthur Ashe Stadium when the world number one faces Russia's 86th-ranked Vitalia Diatchenko.
Read: US Open: Serena Williams chases history at home
The 33-year-old American, who has won 21 of her 60 career Grand Slam starts, completed her second career "Serena Slam" of four major titles in a row by winning last month at Wimbledon.
She would become the first calendar-year Slam winner since Steffi Graf in 1988 by winning the US Open and match Graf for the Open Era career record of 22 Slam titles, two shy of Australian Margaret Court's all-time record.
"I hope she does it," says Roger Federer, the men's career record holder with 17 Slam singles crowns.
"It's intriguing and interesting to see. You don't get this opportunity many times in your career, or in tennis for that matter, so it will be interesting to follow."
Federer won three of four Grand Slam titles in 2004, 2006 and 2007 but never came as close as Williams to completing the sweep, each time falling at the second hurdle on the red clay of Roland Garros.
He lost the 2006 and 2007 French Open finals to Rafael Nadal and fell to Gustavo Kuerten in the third round of the French in 2004.
Aussie legend Rod Laver in 1969 is the last man to win all four Grand Slam titles in a single year.
Read: Tough tests from the start for Federer, Murray at US Open
Federer sees a difference in going for the sweep in best-of-three women's Slam matches versus the men's best-of-five setup.
"Best-of-three matches, it's more of a sprint to the finish line than best of five," Federer said. "There's a little more danger in a best-of-three-set match so that's why she needs to be focused from the very beginning."
And Federer, like Williams, sees a big feat already achieved by her holding all the Slam trophies at the same moment.
"To get it in the same year, I think it's the same as the Serena Slam, in my opinion, but I know people see it differently," Federer said. "It will be very interesting to see."
Top-ranked Novak Djokovic, who missed out on a 2011 calendar Slam with a French Open semi-final loss to Federer, would also be going for a Slam sweep had he beaten Stan Wawrinka in this year's Roland Garros final and completed a career Grand Slam. He is captivated by Williams' run as well.
"I'm sending her good vibes. I hope she does it," he said.
"She is a true champion and she is impressive, what she has managed to do so far at her age, to win three Grand Slams. It's quite incredible."
Read: Nadal feels "very close" to Slam-winning form as Djokovic ponders his own Slam possibilities
Spain's Rafael Nadal, who won the last three majors of 2010 after an Australian Open quarter-final loss, sees Williams' serve as what sets her apart.
"My feeling is she has much more power than the others. That's a big advantage in the girls," Nadal said at Wimbledon.
"There is a difference when she hit the ball than when another hits the ball. For me, Serena makes a difference on the serve and return. First two shots make the difference."
Japanese fourth seed Kei Nishikori, last year's US Open runner-up, said he expects Williams to complete the sweep.
"I know it's going to be a lot of pressure, but I'm sure she is one of the best players in the world," he said. "I hope she can win it."
Read: Nishikori, Ivanovic exit early from US Open
Romanian second seed Simona Halep, who lost to Williams in the Cincinnati final, said the same thing but qualified her support to say she wants to see it only if she isn't the final obstacle in Serena's path.
"If I'm not in the final then I want her to win. If I'm in the final with her, then I want to win," Halep said.
"She has a big chance. I think she has enough power to do that, but of course I want to win.
"I respect her a lot. I've admired her since I was a kid."
Danish fourth seed Caroline Wozniacki, who lost to Williams in last year, feels much the same.
"What she's about to do and what she has done for the sport is amazing," Wozniacki said. "I'm in the other half of the draw so I don't have to worry about it until the final. Hopefully we can do a rerun from last year."
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