Djokovic is trying to become the first man to successfully defend his US Open crown since Roger Federer won five straight from 2004-2008.
It's the last chance for the Serb, who won Olympic singles gold in Paris, to avoid a Grand Slam shut-out this season, after Jannik Sinner won the Australian Open and Carlos Alcaraz bagged both the French Open and Wimbledon titles.
Gauff is aiming to turn things around after struggling to maintain the form that saw her capture a maiden major at Flushing Meadows last year.
AFP Sport looks at three matches to watch on Monday:
Radu Albot vs Novak Djokovic
Serbian superstar Djokovic, fresh off a longed-for Olympic gold medal in Paris, appears poised to ease his way into his US Open title defence with a first-round meeting against qualifier Albot.
The Moldovan, ranked 138th in the world, is 0-11 against top-10 players.
But Djokovic will have some adjusting to do as he closes out the first night session on Arthur Ashe Stadium. The cherished Olympic gold on the clay courts of Roland Garros marked a high point of an otherwise disappointing year for the 24-time Grand Slam champion, who surrendered his Australian Open and French Open titles as well as his top world ranking.
The match will be his first on hard courts since a shot defeat to Luca Nardi in the third round at Indian Wells in March.
Varvara Gracheva vs Coco Gauff
World number three Gauff, whose fortunes have been mixed since she won her maiden Grand Slam at Flushing Meadows last year, will be hoping history repeats itself when she takes on Russian-born French player Varvara Gracheva in the afternoon on Arthur Ashe Stadium.
Their only prior meeting came in the quarter-finals at Auckland in January, Gauff posting a comprehensive 6-1, 6-1 victory and going on to claim the title - so far her only one of 2024.
Gauff has lost three of her past six matches, her second-round exit in her Cincinnati title defence dropping her to third in the world.
The 20-year-old American tried to put a positive spin on that, calling her Cincinnati defeat "a blessing in disguise ... because I was able to actually train, which I hadn't been able to.
"I do my best results when I come off a training block," Gauff said. "I'm having great practices, which doesn't mean I'm going to go out in the match and play great, but it does give you more confidence when you're actually practising great the week before a tournament."
Zheng Qinwen vs Amanda Anisimova
Newly minted Olympic gold medallist Zheng will likely find herself in hostile territory at Louis Armstrong Stadium when she takes on US wild card Amanda Anisimova in the first career meeting between the two.
Having given China a first Olympic tennis gold, Zheng will try again to emulate pioneering compatriot Li Na in claiming a Grand Slam crown - having come up short in the Australian Open final in January.
Anisimova has been on the comeback trail in 2024 after taking a mental health break in 2023. She moved back into the top 50 in the world rankings after reaching her first WTA 1000 final in Toronto two weeks ago.