Before moving to a 2-0 head-to-head record over Musetti, the fourth-seed Greek's last such victory was against Rafael Nadal in the quarter-finals at the 2021 Australian Open.
Tsitsipas needed to draw on that experience and dig deep after only winning 60 per cent of points on his first serve in the first two sets on Tuesday, going on to then win 15 of 17 points in the deciding set.
Post-match, the world number four explained how he needed to isolate his focus on each point and build from there after going two sets down.
"Things don't come easy. I refuse to give up. That's simply how it works with me," Tsitsipas said. "You never really think about getting back after being two sets to love. You just play it point after point. You just wish that your efforts will pay off on a longer scale, longer run.
"Being in that situation, it's a mountain that you have to climb, and I was able to climb it and regain the momentum steadily, but consistently."
The 20-year-old Musetti was able to gain early momentum from the baseline and won the longer points, with an even share of winners as well as forced and unforced errors from Tsitsipas.
The match turned as Tsitsipas regained rhythm on his serve and with more free points coming his way, it then allowed him to apply pressure.
According to Tsitsipas, however, it was far from easy against a tough opponent who is at home on clay.
"He's fighting. He's a talented player that has a very nice one-handed backhand," he said afterwards. "He knows the game on clay. He has grown up playing these courts. He's definitely a difficult opponent to face in any circumstance, really.
"Once I really found my momentum on the serve, my routines and everything, I knew that it can be a different match.
"I felt like I was serving better than him, creating more opportunities with my serve, pressing more. It would have been kind of not fair from my perspective to have a different outcome."