The American world number one and top seed at Flushing Meadows is looking to defend the title she claimed in 2013, and add to her 17 grand slam victories.
Victory at Arthur Ashe Stadium on the second Sunday for Williams would make her home major her most successful - as she has won in New York five times, equal with her Wimbledon and Australian Open efforts.
However, the 32-year-old is on a major drought of sorts, having yet to reach the quarter-finals in a grand slam this year despite competing in all three so far.
Williams said she is motivated by the prospect of reeling in Margaret Court's tally of 24 singles majors.
"It's always motivated me," she said.
"But at the end of the day I have to first get to 18. That's been avoiding me, actually."
Williams' dramatic breakdown at Wimbledon - which saw her double-fault an entire service game in the women's doubles before withdrawing to illness - was one display of her body's vulnerability as she is firmly in the twilight of her career.
However, the flipside is she is also still a force to be reckoned with when fit - as her only loss since London was to her sister Venus in Montreal, in between titles wins in Stanford and Cincinnati.
Williams does have a tricky draw to counter though, with 2011 US Open final conqueror Sam Stosur likely to meet her in the fourth round before a potential clash with eighth seed Ana Ivanovic in the quarter-finals.
Ivanovic downed Williams at the Australian Open in January.
Williams' first assignment in New York will be to tackle wildcard and compatriot Taylor Townsend.
World number two Simona Halep has a fairly blessed draw in the bottom half but is on a collision course with nemesis and fifth seed Maria Sharapova in the last eight.
Sharapova downed Romania's Halep in the French Open final and repeated the dose in another classic three-setter in Cincinnati earlier in the US swing.
The Russian leads their career head-to-head meetings 5-0.
Other possible quarter-finals could pit Angelique Kerber against Agnieszka Radwanska, while the in-form Petra Kvitova could take on Eugenie Bouchard in a Wimbledon final re-match if results go to seeding.
Canada's Bouchard, though, could be set for a slam slump, after making it to the last four of all three majors this season.
The 20-year-old had heavy strapping on her left thigh at the lead-up event in New Haven, and has won just one match since losing the SW19 decider to Kvitova.