This is because his injured left hamstring continues to cause problems.
Fourth seed Djokovic defeated Grigor Dimitrov in straight sets in the third round but fears about the durability of his injured hamstring only grew as the Serbian once again struggled.
All eyes will be on the bandages that drape the left hamstring when the 35-year-old takes on home favourite De Minaur.
Like Djokovic, he has dropped one set in Melbourne so far.
“It’s really difficult to say with Novak exactly what’s happening physically.
“He’s getting the job done, he certainly doesn’t look like he is 100 percent,” seven-times Grand Slam champion John McEnroe said.
Asked if De Minaur could cause issues for Djokovic’s injured hamstring, McEnroe said: “De Minaur is someone potentially (who could do that) because he relies on speed and grit and making an opponent work.
“The type of guy that could cause Novak problems if he is not 100 percent.”
Before Djokovic takes on De Minaur, fifth seed Andrey Rublev will take on Danish teenager Holger Rune.
This is as the Russian bids to reach the quarter-finals at the season-opening major for the second time in three years.
Rublev, 25, believes ninth seed Rune will not be the underdog in their contest, with the Dane a dark horse at the tournament following his Paris Masters final victory over Djokovic in November.
In the other matches, Spanish 24th seed Roberto Bautista Agut will face American Tommy Paul looking to equal his best result in Melbourne, having reached the quarter-finals in 2019.
Ben Shelton will play J.J. Wolf in an all-American clash, with the former competing in the last 16 of a Grand Slam for the first time in his career.
It is a remarkable achievement for the 20-year-old who a year ago was number 569 in the ATP Rankings and still in college.
In the women’s draw, last year’s WTA Finals champion Caroline Garcia will bid for her maiden last-eight berth at the tournament when she comes up against Magda Linette.
Linette is the last remaining Pole after Iga Swiatek and Hubert Hurkacz exited.
Big-hitting Belarusian Aryna Sabalenka, seeded fifth, will aim to stretch her undefeated start to the season against Swiss 12th seed Belinda Bencic.
Bencic is also in solid form with a seven-match winning streak.
Czech 17-year-old Linda Fruhvirtova, the youngest woman left in the draw, will play Croatian Donna Vekic for a place in the quarter-finals as she looks to maintain her fairytale run.
Former world number one Karolina Pliskova takes on Zhang Shuai.