Structure-activity relationship of nanozymes provide ideas for the de novo design of nanozymes. Display omitted Nanozymes, nanomaterials with enzyme-like activities, are becoming powerful competitors and potential substitutes for natural enzymes because of their excellent performance, including design from scratch, controllable activity, and environmental resistance. In recent years, various nanozymes have been discovered or designed, and gradually applied to molecular detection, biomedical treatment and environmental management. Nevertheless, nanozymes are often regarded as fascinating and confusing black boxes as their catalytic mechanisms remain largely indistinct. Interestingly, recent researches have shed light into these black boxes. It appears that the enzymatic activities of nanozymes are closely related to their size, surface lattice, surface modification and composition, etc. Some regular structure–activity relationships have been elucidated in recent reports. In this review, we systematically summarized the studies on the structure–activity relationship of nanozymes in recent years, aiming to illustrate the catalytic mechanism of nanozymes and clarify the key factors regulating their behavior, so as to provide ideas and inspiration for the de novo design of nanozymes.