Under hydrothermal and solvent-thermal conditions, we synthesized two novel polyoxometalate (POM)-based hybrids: [CuI4(Pz)2(H2O)8(PMoVI11MoVO40)]·3.5H2O (1, Pz = pyrazine) and [(C2H8N)5(HPMoVI9MoV3O40)]·DMF·4H2O (2). Single-crystal X-ray diffraction indicates that compound 1 is a three-dimensional structure consisting of Cu (I), {PMo12} anions, Pz, and water, where Cu (I) can be considered as Lewis acid sites. Furthermore, both compounds 1 and 2 possess favorable catalysis activity in catalyzing the conversion of chemical warfare agent simulant 2-chloroethylethyl sulfide (CEES) to nontoxic production of 2-chloroethylethyl sulfoxide (CEESO) under ambient temperature. Significantly, 1 could realize 98% conversion and 100% selectivity of CEES owing to the multisite synergy in the {PMoVI11MoVO40CuI8} units in which the tricoordinated Cu (I) could interact with S and O atoms from CEES and H2O2, respectively. This interaction not only decreases the distance of CEES from peroxomolybdenum species formed by H2O2 but also activates CEES.