Fritz is the highest-seeded US player in the men's draw and has yet to drop a set at the year's final Grand Slam but he will face his toughest test yet against an opponent he has never beaten in seven meetings.
The ninth seed, who has never got this far at a US Open, said he had no plans to change his game when he closes out the day session at Arthur Ashe Stadium against three-time champion Djokovic.
"I think I need to trust that if I'm playing well, then that's going to be enough, and I don't need to kind of do anything extra," said Fritz.
"Novak's Novak. It's tough, he's got (beat) me seven times. There's no one on tour that has any kind of a record like that against me, so I'm hoping one of these times I've got to get him. US Open quarters would be a pretty good time to get him."
In their most recent meeting, Djokovic beat Fritz last month in the quarter-finals of a US Open tune-up event in Cincinnati that the Serbian went on to win by beating Carlos Alcaraz.
Djokovic, who is seeking a 24th Grand Slam title to equal Margaret Court's record, has enjoyed a mostly smooth passage in New York apart from a third-round clash against compatriot Laslo Djere when he had to come back from two sets down.
There have been 78 Grand Slams played since Andy Roddick won the 2003 US Open and hopes that an American man can snap that title drought at one of the sport's blue-riband events have fallen largely on the shoulders of Fritz and Frances Tiafoe.
Should Fritz prevail over Djokovic it would set up an all-American semi-final against the winner of the late match at Arthur Ashe Stadium between 10th seed Frances Tiafoe and unseeded Ben Shelton.
Tiafoe enjoyed a run to the US Open semi-finals in 2022 and, while he failed to replicate that at the year's first Grand Slams, has again looked comfortable on the New York hardcourts having dropped just one set en route to the quarter-finals.
American Gauff will kick off the action on Arthur Ashe Stadium in a clash with Jelena Ostapenko (26), the Latvian 20th seed and former French Open champion who is fresh off a straight sets win over world number one Iga Swiatek.
Gauff's lead-up to the US Open included hardcourt titles in Washington and Cincinnati and the sixth seed has shown great tactics and maturity in New York where she appears to be peaking at the perfect time in search of a maiden Grand Slam title.
The day's other women's quarter-final sees Czech 10th seed and French Open finalist Karolina Muchova facing Romanian 30th seed Sorana Cirstea.
