World number one Carlos Alcaraz faces a potential quarter-final clash with old foe Jannik Sinner in his US Open title defence, and American Coco Gauff is on a collision course with defending champion Iga Swiatek on the women's side.
Alcaraz faces German Dominik Koepfer in his opener and should have few issues in the early rounds and the Wimbledon champion will likely face his first tough test against Sinner, the 22-year-old Italian who knocked him out in this year's Miami semi-finals.
Djokovic, a 23-times major champion, is back after US COVID travel restrictions meant he was unable to travel to New York in 2022 and will first play France's Alexandre Muller before potentially meeting seventh-ranked Greek Stefanos Tsitsipas in the final eight.
Elsewhere in the draw, former winner Daniil Medvedev could face Russian compatriot Andrey Rublev in the quarters, while American Frances Tiafoe could play last year's runner-up Casper Ruud and fourth seed Holger Rune if he matches last year's run to the semis.
Gauff will try to recreate the magic of her Cincinnati win this month, where she beat Swiatek en route to the title, and the pair could meet in the final eight.
Swiatek will open her campaign against Sweden's Rebecca Peterson.
The bottom half of the draw presents a tantalising possible quarter-final showdown between Tunisian Ons Jabeur, a finalist 12 months ago, and second seed Aryna Sabalenka, who collected her maiden major title at this year's Australian Open.
Gauff's compatriot and frequent doubles partner Jessica Pegula, the third seed, faces a tough draw as she opens against Italian Camila Giorgi and could also meet 2022 WTA Finals winner Caroline Garcia of France.
