Nanozymes are nanomaterial-based enzyme mimics that have dominated recent research because of their remarkable catalytic activity, stability, and low cost. Among them, CeO2 nanomaterials (CeO2 NMs) possess distinct physicochemical properties and inherent catalytic properties mimicking oxidase (OXD), peroxidase (POD), catalase (CAT), superoxide dismutase (SOD), phosphatase, nuclease, and photolyases. The surface valence state, Ce4+/Ce3+ conversion, and oxygen vacancies (OVs) on the surface of CeO2 NMs are closely associated with enzyme-like activities. Surface modification (ions, small molecules, and macromolecular capping) can strongly promote or inhibit their catalytic activities. CeO2 NMs have emerged as attractive materials for biochemical applications including biocatalytic conversion, pollutant destruction, antimicrobial therapies, biosensors, and disease therapies. We summarize here the development history, catalytic mechanisms, and surface modification methods of CeO2 mimetic enzymes and the exploration of their applications as alternatives to natural enzymes in biochemical fields. Further, we outline potential challenges and prospects and hope to provide better guidance for the design and application of these promising artificial enzymes.