The American went into Wimbledon without a grand slam crown in two years and having lost in the first round of the French Open, but she swept any doubts aside to win her fifth title at the All England Club.
Three weeks later she returned to SW19 for the Olympics and put together one of the most dominant weeks in tennis history, losing only 17 games in six matches to win her first singles gold medal.
Her 6-0 6-1 demolition of Maria Sharapova in the final was remarkable and she then added the doubles title with sister Venus to give both women a record fourth Olympic gold medal.
Serena may only be the fourth seed in New York but there is no doubt she is the one to beat, and the 30-year-old said: "You've got to embrace it whether you're the favourite or the one to beat or whether you are not.
"And I embrace it. In Wimbledon I wasn't the favourite, I embraced that. Hopefully I can do my best here.
"I don't feel pressure. My dad said the only pressure you have is the pressure you put on yourself. If I win, that would be great. If I lose, I realise I'm going to go home and be devastated. But there's always tomorrow."
Serena is hoping to go one better than at Flushing Meadows last year, when she surprisingly lost in the final to Sam Stosur.
Victory here would give the American her 15th grand slam singles title, still seven behind Steffi Graf's Open era record of 22, but Kim Clijsters puts Serena at the top of the tree.
Clijsters, who will retire after the US Open, said: "To me Serena is the best ever because physically she just stands out.
"She's fast, she's strong, she has a very good eye as well. What we have seen over the last few months is the best player ever.
"I feel very lucky that I have been able to be a part of a big generation where Venus and Serena kind of raised women's tennis to a completely different level. It's been an absolute honour to be a part of that."
And Serena may not be the only Williams sister challenging for the title this year.
Venus' career looked in serious danger when she revealed at the US Open last year that she was suffering from the auto-immune disease Sjogren's Syndrome and she was a shadow of her former self when she lost in the first round at Wimbledon.
But the 32-year-old showed encouraging signs at the Olympics and last week reached the semi-finals of the Premier event in Cincinnati.
Williams revealed she first felt the symptoms of Sjogren's Syndrome in 2007 and was told by one doctor to go and see a psychiatrist.
She said: "Last year it was definitely a tough year. I've come a long way in that one year. It's great to be back and feeling a lot better. Now I feel like I can play. Last year was just a real struggle.
"This year when I practise I don't want to quit. It's a huge difference. To be in a major and just want to walk off the court is tough. I have come a long way thanks to my doctors and everything else. It's great."
Venus has no doubt who will be the player to beat in New York, though, saying of her sister: "She's amazing. I think when she's playing great and feeling confident - even when she isn't - it still takes a hurricane to beat her."
Sharapova should be another player in contention for the title. The Russian has not played since the Olympics because of a stomach bug but declared herself fit and healthy.
The world number three completed her career grand slam by winning the French Open in June and now has her sights on reclaiming the title she won six years ago.
Sharapova said: "I have had an incredible year so far. Obviously winning the French was very meaningful to me. It was just one that I really wanted to get and to be part of my career whenever I ended.
"And being there first time as an Olympian, going out there and getting silver, that was a great moment.
"Of course this is the last big one. This is where you have to put all your energy. There's no reason why I shouldn't perform my best here."
Defending champion Stosur opens proceedings on Arthur Ashe Stadium on Monday against Croatia's Petra Martic while Sharapova meets Melinda Czink of Hungary before Clijsters kicks off the evening session against American Victoria Duval.
World number one Victoria Azarenka is also in action on Monday on Louis Armstrong Stadium against Russia's Alexandra Panova.