The Italian was the first man through to the fourth round after pulling off a stunning five-set comeback against Hungarian Marton Fucsovics, prevailing 4-6 4-6 6-1 6-2 6-0.
In the process, he teed up a blockbuster final-16 clash with Greek star Tsitsipas who eased past Dutchman Tallon Griekspoor in straight sets shortly after, winning 6-2 7-6 (7-5) 6-3.
Both players are eyeing their maiden grand slam.
Tsitsipas, 24, was the 2021 runner-up at Roland Garros and is a three-time Melbourne Park semi-finalist while 21-year-old Sinner has made it to the quarter-finals of every slam.
Tsitsipas has a 4-1 record against Sinner, including a straight-sets quarter-final victory at last year's Open.
Sinner, who has Australian super coach Darren Cahill in his team, was in dire straights after dropping the opening two sets against Fucsovics before turning things around dramatically.
He reeled off the first five games of the third set and dropped just three games in total across the final three sets.
"Obviously, I had to change something in my game after the two sets," Sinner said.
"I was feeling the ball quite well also in the beginning but the final shots I was missing a little bit, also tactically I was not so good.
"Obviously made a lot of work in the off-season especially physically and today I was good physically also in the last set.
"Let's see what is going to happen in the next round."
He relished having Cahill among his coaching staff as he eyed a deep run at Melbourne Park.
"It's very nice to have him here," Sinner said.
"Obviously, he's a very important part of my team but the most important thing is he fits together with the rest of the team and I'm very happy to have them.
"Without them, it's impossible to play at such a high level.
"We work every day harder - so let's go."
Sinner will need every edge he can get against Tsitsipas, who is enjoying an unbeaten summer and had a far more straight-forward third-round victory.
A second-set tiebreak was the closest he came to being challenged while he didn't drop any of his 15 service games.
"Fair crack of the whip, mate. I mean, it was great," he said.
"It was a good mixing up today. Mixing up my slice, opening up the court, I think my placement on the serve was exceptional today.
"I didn't have a lot of rallies on my serve which helped a lot today, (kept) things clean."
8°C