The mimicking enzyme activities of eighteen classic POMs with different structures, Keggin (H3PW12O40, H4SiW12O40, H4GeW12O40, K4GeW12O40, H3PMo12O40, H4SiMo12O40 and Eu3PMo12O40), Wells-Dawson (H6P2Mo18O62, α-(NH4)6P2W18O62 and α-K6P2W18O62·14H2O), lacunary-Keggin (Na8H[α-PW9O34], Na10[α-SiW9O34], Na10[α-GeW9O34] and K8[γ-SiW10O36]), the transition-metal substituted-type (α-1,2,3-K6H[SiW9V3O34] and H5PMo10V2O40), sandwich-type (K10P2W18Fe4(H2O)2O68) and an isopolyoxotungstate (Na10H2W12O42) were screened and compared. The mechanisms and reaction conditions of POMs with mimicking enzyme-like activities were also analyzed. The results shown that the structures, the hybrid atoms, the coordination atoms, the substituted metal atoms, pH and substrate are the effect factors for the enzyme mimic activities of POM. Among the eighteen POMs, H3PW12O40, H4SiW12O40, H4GeW12O40, α-(NH4)6P2W18O62, α-K6P2W18O62·14H2O, Na8H[α-PW9O34], Na10[α-SiW9O34], Na10[α-GeW9O34], K8[γ-SiW10O36], K10P2W18Fe4(H2O)2O68 and Na10H2W12O42 had the peroxidase activities. Eu3PMo12O40, H3PMo12O40, H4SiMo12O40, α-1,2,3-K6H [SiW9V3O34], H6P2Mo18O62 and H5PMo10V2O40 showed the oxidase-like activities. K4GeW12O40 did not show the peroxidase and oxidase activities. The Na8H[α-PW9O34], Na10[α-SiW9O34] and Na10[α-GeW9O34] showed intrinsic enzyme activities at alkaline conditions, which were different from other type of POMs. The sandwich-type K10P2W18Fe4(H2O)2O68 displayed the strongest peroxidase activity, which is similar to natural horseradish peroxidase.