In the first round, Maria Sharapova will face a very tough opponent as she will play the second seed, Simona Halep.
The Russian, 30, returns to Grand Slam action for the first time since completing a 15-month anti-doping suspension.
After going 41/2 years without collecting a major championship, now firmly in his mid-30s, he heads into Monday's start of the U.S. Open with a chance to win his third such trophy of 2017.
Sharapova tested positive for the drug meldonium in 2016, which had been added to the World Anti-Doping Agency's banned substances list in January of that year.
That leaves Federer and top seed Rafael Nadal as the clear favourites, with the pair in line for a potential semi-final meeting.
The absence of Serena Williams has created an opportunity at the top of the WTA rankings, and the fact no fewer than eight women can leave the last Grand Slam of the season as world No 1 makes for the kind of logjam usually only seen amongst yellow taxis queuing in the streets around Times Square.
The potential men's quarterfinals: Nadal against Grigor Dimitrov, Federer against Dominic Thiem, Murray against Jo-Wilfried Tsonga, and Zverev against 2014 champion Marin Cilic.
On the top half of the bracket, the quarterfinals could be No. 1 Karolina Pliskova against 2004 U.S. Open champion Svetlana Kuznetsova; and Kerber or Ostapenko against Elina Svitolina or Madison Keys. They have played 37 head-to-head matches, including 12 at major tournaments - at least twice in a final - but never at the Flushing Meadows in any round.
A hip injury has seen Andy Murray join Novak Djokovic, Stan Wawrinka, Milos Raonic and Kei Nishikori on the list of absentees. Pliskova, still searching for her first Grand Slam win, will take on Magda Linette in her opener.
Sharapova was refused a wildcard by French Open organizers and missed Wimbledon with a thigh injury. She has also been a semi-finalist at Wimbledon and the US Open, yet thus far, she has failed to pick up one of the landmark titles.
Kerber beat Pliskova in last year's final in NY to reach No. 1. "I am different in all the ways", she said.
Either way, as long as Sharapova remains in the field at the tournament that begins Monday, she will be a main topic of conversation. Bellis has been solid, if unseeded, in her first full year on tour.
More young blood breaking into the top 32 seedings are teenage Ana Konjuh and 21-year-old Anett Kontaveit, while 23-year-old Gavrilova has just won her first title in CT. "Sometimes I feel like, Oh, there is a shop, like, three blocks away, and three blocks is unbelievable, long, and I'm so exhausted".
Blockbuster clashes are usually reserved for the second week of grand slams, but the opening day will have its very own showstopper.