Improving greatly the separation efficiency of interfacial charge carrier is a major challenge in photocatalysis. Herein, a new class of C60-mediated NH2-MIL-125(Ti)/Zn0.5Cd0.5S S-scheme heterojunction with enhanced interfacial charge carrier separation is designed and synthesized. The constructed S-scheme heterojunction thermodynamically favors photocatalytic H2 evolution because of the large driving force resulting from its strong redox abilities. As a consequence, the optimum proportion of C60-mediated NH2-MIL-125(Ti)/Zn0.5Cd0.5S S-scheme heterojunction displays comparable H2 evolution activity with a rate of 7825.20 µmol h−1 g−1 under visible light irradiation, which is about 93.05 times, 6.38 times and 2.65 times higher than that of 2% C60/NH2-MIL-125(Ti), Zn0.5Cd0.5S and 45% NH2-MIL-125(Ti)/Zn0.5Cd0.5S, and outperforms the majority of the previously reported MOFs-based photocatalysts. Spectroscopic characterizations and theory calculations indicate that the S-scheme heterojunction can powerfully promote the separation of photogenerated carriers. This work offers a new insight for future design and development of highly active MOFs-based photocatalysts.