The 34-year-old US superstar matched Steffi Graf's Open Era record of 22 Grand Slam singles titles with her triumph at Wimbledon in July.
With a seventh US Open triumph she can break Graf's record, and continue her march toward Australian Margaret Court's all-time mark of 24 Grand Slam titles.
She could also break Graf's record of 186 consecutive weeks atop the world rankings, and surpass Chris Evert for most US Open singles titles won in the Open Era. But after seeing a frustrating year go by between her 21st Grand Slam win and No. 22, Williams said she'd learned to let history take care of itself.
"I learned not to get involved in those debates and conversations," Williams said after her straight-sets victory over Angelique Kerber in the Wimbledon final.
"I definitely had some sleepless nights ... I've just felt a lot of pressure."
When the final Grand Slam of the year gets underway on Monday, the pressure could be on again. Williams's bid to retain her Olympic singles title ended in Rio de Janeiro this month when she was sent crashing out of the third round by Elina Svitolina.
Williams was clearly hindered by the shoulder injury that had forced her out of the Montreal WTA tournament as she served up eight double faults and 37 unforced errors in the straight-sets defeat.
Since then she has withdrawn from her WTA title defence in Cincinnati, saying the inflammation in her shoulder "continues to be a challenge".
If Williams isn't at full strength, Kerber is just one of the players poised to pounce.
Kerber closing in
The German defeated Williams in the Australian Open final in January. Seeded second in New York, she is one of three players with a chance to seize the number one ranking if Williams falters.
Kerber, 28, boasts a title at Stuttgart, an Olympic silver medal and finals appearances at Brisbane in January and this month in Cincinnati -- where she missed her first chance to supplant Williams atop the rankings.
Being viewed as a legitimate threat to Williams, Kerber said, "is really special". "Because Serena is one of the best players and athletes in the world," she said.
"Of course it's really special that a lot of people are speaking about her and then speaking about me.
"Third-seeded Spaniard Garbine Muguruza also has a shot at the top, although the 22-year-old who stunned Williams in the French Open final will need her best US Open ever to do so.
In three main-draw appearances she has won just one match. Turning around her Flushing Meadows fortunes would further her aim of establishing herself as more than "the girl that beat Serena" at Roland Garros.
"I want to really do well there," the Spaniard said. "Hopefully this is the year."
Fourth-seeded Agnieszka Radwanska of Poland also has an outside chance at the world number one ranking if she can claim her first Grand Slam title.
Like Radwanska, Romanian fifth seed Simona Halep is seeking a Grand Slam breakthrough while sixth-seeded Venus Williams, who counts two US Open victories among her seven Grand Slam singles titles, is one of a handful of former champions among the seeds.
That includes 2004 winner Svetlana Kuznetsova of Russia and Australian Samantha Stosur -- who toppled Serena in the 2011 final. Last year's US Open champion Flavia Pennetta of Italy will not defend her title after retiring at the end of last year.