Ahead of a tilt at the French Open, for which he is among the favourites, world No.5 Tsitsipas has been tuning up his game at this week's ATP 250 tournament.
The Greek star was sharp in posting a 6-3 6-4 win over Japan's Yoshihito Nishioka, and 19-year-old Italian Musetti awaits him on Sunday (AEST).
Tsitsipas dropped just four games when he crushed Musetti in an Acapulco semi-final in March, but he senses more of a threat this time from the exciting youngster.
"We played in different conditions. Acapulco was a hardcourt match and with altitude," Tsitsipas said. "The conditions here are different. He's someone who enjoys playing on clay.
"We share a similar game style I think with a one-handed backhand, which is beautiful to see, but tomorrow it's going to be serious business I knew he can play good on this surface. I know he can elevate his game, so it's important for me to be in the semi-finals."
Musetti overcame Slovenian Aljaz Bedene 6-3 7-6 (7-2) in their quarter-final, scrambling through a chaotic second set in which he trailed 5-2 at one stage but then reeled off four straight games, only to fail to serve out.
Thankfully for the youngster, he pulled through the tie-break.
"It was a crazy end," Musetti said. "I was 6-5 up, and at 30-30 played a really bad volley and hit an underarm serve. Sometimes I go out of my mind. I am really proud of myself as I was 2-5 down in the second set and I stayed focused. I tried to play each point at my best."
Russian Karen Khachanov marked his 25th birthday with a 6-1 7-6 (7-3) win over Frenchman Richard Gasquet, veteran doyen of the single-handed backhand.
Khachanov faced a wait to learn who he must face in the semi-finals, however, with Cameron Norrie and Arthur Rinderknech level at one set all overnight, after rain forced an early end to play.
At the Geneva Open, Norway's Casper Ruud will tackle Canadian Denis Shapovalov in Sunday's (AEST) final.
Ruud saw off Spaniard Pablo Andujar 6-3 6-2, while Shapovalov earned a 6-4 7-5 win against Uruguayan qualifier Pablo Cuevas.