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Recently, remarkable progress has been made in nanozyme research due to the rapid development of nanomaterials. Two-dimensional nanomaterials such as metal nanosheets, graphene-based materials, transition metal oxides/dichalcogenides, etc., provide enhanced physical and chemical functionality owing to their ultrathin structures, high surface-to-volume ratios, and surface charges. They have also been found to have high catalytic activities in terms of natural enzymes such as peroxidase, oxidase, catalase, and superoxide dismutase. This review provides an overview of the recent progress of nanozymes based on two-dimensional nanomaterials, with an emphasis on their synthetic strategies, hybridization, catalytic properties, and biomedical applications. Finally, the future challenges and prospects for this research are discussed.