The selective oxidation of C-H bonds of benzylic compounds to synthesize high-value-added ketones remains a challenge under mild conditions, and the ambiguity of its oxidation mechanism limits the further development of this field. In this work, we construct a polyoxometalate-based metal-organic framework (POMOF), Cu I 2 Cu II (bix) 2 {V 4 O 12 } ( 1 , bix = 1,4-bis(imidazole-1-ylmethyl)benzene), successfully achieving the efficient oxidation catalysis of various benzylic compounds with outstanding conversion, selectivity and durability under mild conditions. Our experimental studies suggest that the highly catalytic activity of 1 derives from its attractive structure with multiple active sites, which consists of V V centers in a unique U-type {V 4 O 12 } 4− ({V 4 }) cluster and Cu I and Cu II centers bridged to the {V 4 } cluster. Importantly, further theoretical calculations indicate that there exists synergistic catalysis between Cu I /{V 4 } sites and Cu II /{V 4 } sites for 1 as catalyst in the oxidation of benzylic compounds, where the {V 4 } cluster mainly provides deprotonation and oxidation sites, and the Cu I site plays a role in the reduction of the oxidant, while the Cu II site plays a role in the adsorption of the oxidant. This is the first POMOF whose catalytic mechanism towards the oxidation of benzylic C-H bonds is deeply studied through the combination of experiments and theoretical calculations, providing a new perspective for the design of related catalysts. Multi-active site synergy in a polyoxovanadate-based mixed-valence copper metal-organic framework for efficient catalysis of C-H bond oxidation of benzylic compounds.