But after her Wimbledon and Olympic triumphs, many of her rivals seem to think the year's final grand slam is hers to lose.
"Serena is probably the favorite coming in given her recent form," said Australian Samantha Stosur, the defending champion. "No matter who you are, I don't think you can really deny that."
Kim Clijsters, a three-time U.S. Open champion is playing in the last tournament of her career, also tipped her hat to Williams.
"Serena is the best ever just because physically she just stands out," Clijsters told reporters. "When she's in good shape she just stands out tremendously. "I mean, she's fast, she's strong, she has a very good eye, as well. It's the combination. What we have seen over the last few months is the best player ever."
Williams lost in the round of 16 at the Australian Open, was bounced in her first match at the French before returning to the form that has seen her claim 14 grand slam championships.
The three-time U.S. Open champion is taking her status as the favorite in stride.
"You've got to embrace it whether you're the favorite or the one to beat or whether you are not," she said. "And I embrace it. In Wimbledon I wasn't the favorite. I embraced that.
"Hopefully I can propel and do my best here."
ANYTHING CAN HAPPEN
Top-ranked Azarenka, who won the Australian Open earlier this year by beating Sharapova in the final, bristled at the talk Williams was the one to beat.
"When I go in the tournament I'm trying to think of just the girl or my opponent who I play today, you know, that particular day," said the 6-foot-tall (1.83 m) Azarenka, who will face Russian Alexandra Panova in the opening round.
"Because the tournament is really long anything can happen on any day. You cannot feel great throughout the two weeks and play perfectly every match.
"You just have to take it really one moment at a time and don't think what's going to happen later or who's the favourite or not. I never even think about that."
Sharapova, a four-times grand slam champion, admitted Williams "gained a tremendous amount of confidence at Wimbledon" before striking gold at the London Games.
"When she got to the Olympics with every match she just improved," said Sharapova. "She took that confidence and she played just really great physical tennis, served extremely well.
"Who knows? Obviously of course she's the favorite because she won those two big events back to back. But everybody is still in the draw here.
"It starts from the first round on, and that's why everybody is here."
Barring an upset based on the seeding, Williams would play Radwanska in one semi-final, while Azarenka could take on Sharapova in the other.
Williams, who last won the U.S. Open in 2008, said it was difficult to compare winning the Olympics as a member of the United States team with a victory at Flushing Meadows.
"The Olympics is a totally different thing because you're playing for your country and you're rooting on your team mates and stuff like that," she said. "So it's just super, super cool.
"It's like Olympics is almost more fun. Whereas you really want to win but if you don't then you want the USA to win. Now here it's back to being a one-person sport." (Editing by Amlan Chakraborty)