The 24-time major winner has been bumped from the night match on centre court to an afternoon session, with the primetime evening slot going to second seed Sinner.
Italy’s Sinner meets dangerous American eighth seed Ben Shelton, with the winners playing for a place in Sunday’s Melbourne final.
Iga Swiatek takes on Elena Rybakina and Jessica Pegula tackles Amanda Anisimova in women’s quarter-final action preceding the men on Rod Laver Arena.
Ten-time Australian Open champion Djokovic got a free ride into the Musetti showdown when rising Czech star Jakub Mensik pulled out injured, giving the 38-year-old Serb an extra day’s rest.
“Pretty sure he won’t be tired,” said the fifth-seeded Italian Musetti.
“But hopefully the rhythm that I have right now… will bring me luck for the next one. I feel ready to try to push him to his maximum,” Musetti said.
The odds are stacked against Musetti, who is into the last eight at Melbourne for the first time, with clay and grass his usual forte.
He has played Djokovic 10 times before – and only beaten him once, back in 2023.
Sinner is bidding to win the Melbourne crown for a third time in a row, something only Djokovic has done in the Open era (since 1968).
He has a tough opponent in Shelton, who reached the semi-finals last year – where he lost in straight sets to Sinner.
The pair have met nine times, with the world number two winning eight of them.
However, Shelton is a fan favourite and is hoping to harness the energy of a “rowdy” crowd to pull off a shock.
“I’m definitely a competitor, I’m rowdy on court, I look forward to rowdy crowds,” he said.
Six-time Grand Slam champion Swiatek is chasing a maiden Melbourne title and knows the game of fifth-seeded Kazakh Rybakina well.
The pair, who open the day’s action, have faced each other many times, with Swiatek holding a 6-5 advantage.
“Every match she’s been a tough opponent, and her tennis for sure is great,” said the Polish world number two.
“I need to be 100% ready and go for it and use my experience and also the knowledge from previous matches,” she said.
Whoever wins will have sixth seed Pegula, who ousted defending champion Madison Keys, or fellow American and fourth seed Anisimova waiting for them.