Greek second seed Tsitsipas, who triumphed at the Monte Carlo Country Club in the last two editions, was never in the mix against Fritz, who reached the last four of a Masters event for the first time.
Tsitsipas was then followed out of the tournament on Friday by third seed Daniil Medvedev, who lost 6-3 6-4 to Denmark's Holger Rune.
It means the top three seeds have now been knocked out of the clay-court tournament following 22-time grand slam champion Novak Djokovic's exit in the third round on Thursday.
Tsitsipas was on a 12-match winning streak on the Cote d'Azur, where he claimed his two Masters 1000 titles, but eighth seed Fritz raced to a 4-0 lead in the opening set, which he wrapped up by winning his service game to love.
Tsitsipas improved slightly in the second set, only for Fritz to break decisively for 4-3 with a winner.
He then held firm to set up a semi-final meeting with Russian Andrey Rublev, who earlier overcame some second-set nerves to dispatch German qualifier Jan-Lennard Struff with a 6-1 7-6 (7-5) victory.
"I stuck to the strategy of pulling the trigger and not letting him dictate with his forehand," said Fritz.
"Beating him here gives me a lot of confidence. It's given me the reassurance I need to know I can play well on clay."
Medvedev, who saved two match points when he beat Alexander Zverev on Thursday, was distracted by the crowd at the end of the first set and spoke to the umpire about it.
He broke back to 2-2 in the fourth game of the second set, but swiped his racket on the ground in frustration after losing the match and failing to reach his sixth straight final this year, having won four titles in 2023.
"I have huge respect for everything he's done," Rune said. "It was not easy to stop him but I'm happy I managed to do it."
Rune, who staged a comeback to beat Djokovic and win the Paris Masters last November, is aiming for his first title of the year.
The 19-year-old Dane next plays 21-year-old Italian Jannik Sinner, who eased past Djokovic's conqueror Lorenzo Musetti 6-2 6-2 in an all-Italian quarterfinal.
"I felt great today on the court. I'm hitting the ball in the right spots in the right moments," Sinner said. "I tried to stay aggressive, which I've done."
Sinner broke Musetti twice in the second set and converted his first match point with a strong first serve that Musetti returned long.
With AP
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