Organisers announced the entries into this year's final Grand Slam tournament on Thursday with the field to be led by the current world number one, who beat Victoria Azarenka in last season's final.
Williams is one of five previous winners of the Flushing Meadows title, the others being Sam Stosur, Maria Sharapova, Svetlana Kuznetsova and her own sister, Venus.
Last year's champion is also one of 10 Americans in the field - the most players from any single nation.
Ninety-eight of the world's top 100 players are due to compete, with Romina Oprandi (shoulder) and Garbine Muguruza (foot) out due to injury.
World number 102 Dinah Pfizenmaier is the last player to gain direct entry.
Alisa Kleybanova, Aleksandra Wozniak, Petra Cetkovska and Alexandra Dulgheru will all play under a protected ranking following spells out of the game.
Kleybanova will be competing in her first Grand Slam tournament since overcoming her battle with cancer. She was diagnosed with Hodgkin's Lymphoma in 2011, the same illness that British doubles star Ross Hutchins is currently fighting.
The field will be completed by 16 qualifiers and eight wild cards.
The tournament takes place from August 26 to September 9. This year the women's singles final is scheduled to take place on the second Sunday - September 8.
The men's field was announced on Wednesday.