Both oxygen vacancies and surface chemistry can affect the enzyme-like catalytic activities of CeO2-based nanozymes. However, the mechanism of the enzyme-mimetic process is not yet clearly elucidated, which is of great importance to guide the synthesis of high-performance nanozymes with desirable properties. Herein, we report a facile one-pot solvothermal method for the preparation of polyvinylpyrrolidone (PVP)-capped CeO2 nanoflowers with adjustable oxygen vacancies by changing appropriate solvothermal reaction parameters. Oxygen vacancies effectively increase under a higher precursor concentration, extended solvothermal time, and proper reaction temperature. The maximum content of surface Ce(iii) cations is up to 50% for 31.1 nm CeO2 nanoflowers, which exhibit 0.07 mM apparent Michaelis constant towards 3,3',5,5'-tetramethylbenanozymeidine and show a higher binding affinity than the other CeO2-based catalysts. Theoretical results indicate that the synergy between PVP and oxygen vacancies can significantly promote the adsorption of O2 and TMB on CeO2, which directly enhances the oxidase-mimetic activity of flower-like CeO2 nanozymes. This work can shed light on a new perspective on the enzyme-like performance promotion of CeO2-based catalysts and surface engineering of nanozymes.