Non-neoplastic diseases, such as cardiovascular, neurodegenerative, metabolic, and inflammatory disorders, are major global health challenges with complex pathophysiologies that demand precise and innovative therapeutic strategies. Nanozymes, artificial nanomaterials with enzyme-like catalytic functions, have recently emerged as promising candidates for such interventions. Distinguished by their programmable structures, tunable activities, and excellent biocompatibility, nanozymes can mimic multiple natural enzymes (e.g., superoxide dismutase, catalase, and peroxidase) to modulate oxidative stress and inflammation. Beyond catalytic activity, their functional integration enables immune regulation and metabolic reprogramming, facilitating multi-level (molecular to tissue) microenvironmental remodeling. This review highlights recent progress in nanozyme development for non-neoplastic disease therapy, emphasizing structure–function relationships, activity regulation in pathological conditions, and mechanistic roles in disrupting the oxidative stress–inflammation–immune dysregulation loop. We further summarize representative applications across cardiovascular diseases, neurodegenerative conditions, metabolic disorders, and inflammatory pathologies, focusing on advances in targeted delivery, responsive release, and multimodal theranostics. These insights collectively underline the transformative potential of nanozymes in next-generation precision medicine.