Top-seed Fritz, the highest-ranked American in the world at number 10, lost 0-6, 6-4, 7-6 (7/2) to the Japanese wild card, who went into the tournament without a tour-level win to his name.
Mochizuki quickly took control in the tiebreaker and closed the match out with a volleyed smash at the net to delight the Tokyo crowd.
His quarter-final opponent will be Australian Alexei Popyrin, who beat Chile’s Cristian Garin 4-6, 7-6 (7/3), 6-2.
Number four seed Alex de Minaur progressed to the quarter-finals with a 6-0, 7-5 win over Argentina’s Diego Schwartzman.
Russia’s Aslan Karatsev also advanced to the quarter-finals with a 6-3, 6-4 win over China’s Zhang Zhizhen.