Nanozymes, a class of nanomaterials with intrinsic enzyme-like characteristics, have emerged as promising alternatives to natural enzymes, owing to their cost-effectiveness, exceptional stability, tunable catalytic activity, and scalable production capability. The pioneering discovery of peroxidase mimic has sparked widespread interest in artificial enzymes, propelling significant advancements in the field of nanomedicines. However, the clinical translation of these agents is significantly impeded by inherent nanotoxicity concerns stemming from persistent bioaccumulation in living systems. The emergence of biodegradable nanozymes has made it possible to fully address this challenge while maintaining therapeutic efficacy. A comprehensive understanding of the enzyme-mimicking catalytic mechanisms is essential for expanding diagnostic and therapeutic applications. Furthermore, elucidating the in vivo metabolic fate of biodegradable systems is crucial for improving biosafety and reducing immunogenic risks. This review systematically summarizes three fundamental aspects: (1) the degradation pathways of biodegradable nanozymes, (2) enzyme-mimetic activities and catalytic mechanisms, and (3) recent advances in biomedical applications spanning diagnostic imaging and therapeutic interventions. Additionally, the current opportunities and technical challenges in developing biodegradable enzyme-mimicking nanocatalysts are discussed. By addressing these critical aspects, this review aims to accelerate the rational development of biodegradable nanozymes with optimized biosafety profiles, ultimately bridging the gap between laboratory innovation and clinical implementation in precision medicine. STATEMENT OF SIGNIFICANCE: Biodegradable nanozymes offer a promising solution to persistent bioaccumulation toxicity, while maintaining enzyme-mimicking activities and serving as cost-effective, stable alternatives to natural enzymes. With recent progress in the biomedical field, this review provides a comprehensive analysis of their degradation pathways, catalytic mechanisms, and biomedical applications. It also outlines the remaining challenges that impede the rational design of nanozymes and their successful clinical translation. A deeper understanding of the degradation behavior and catalytic mechanisms of biodegradable nanozymes in this review will be valuable in advancing their development as safe and effective nanocatalysts for precision medicine.