**Abstract:** Nanozymes, characterized by their enzyme-mimicking properties, have emerged as promising alternatives to natural enzymes due to their exceptional attributes such as regulation of oxidative stress, convenient storage, adjustable catalytic activities, remarkable stability, and scalability for large-scale production. Given the potent regulatory function of nanozymes on oxidative stress and the role of reactive oxygen species (ROS) in metabolic diseases, nanozymes offer a unique perspective for therapy through multifunctional activities, achieving essential results in the treatment of metabolic diseases by directly scavenging excess ROS or regulating pathologically related molecules. This review discusses rational design strategies, nanozyme-enabled therapeutic mechanisms at the cellular level, and the application of nanozymes in treating several typical metabolic diseases, including obesity, diabetes, cardiovascular disease, and diabetic wound healing. Additionally, the pharmacokinetics, safety analysis, challenges, and outlooks for the application of nanozyme are presented. **Keywords:** Nanozyme, Metabolic disease, Inflammation, Oxidative stress, Glucose homeostasis Nanozymes, characterized by high catalytic efficiency, stability, cost-effectiveness, and scalability, have found widespread applications in various fields. The concept of nanozymes was first proposed in 2004 and has since been extensively studied for their enzyme-like activities. Metabolic diseases, such as obesity, diabetes, and cardiovascular disorders, pose significant global health challenges. These diseases are characterized by impaired metabolic processes, including increased body weight, blood glucose, insulin resistance, inflammation, and oxidative stress. Traditional approaches to managing these diseases have limitations in terms of safety and efficacy, highlighting the need for innovative strategies. Nanozymes offer several advantages over traditional methods, including tunable properties, biocompatibility, biodegradability, targeted drug delivery, and cost-effective production. This review focuses on the rational design strategies and cellular-level mechanisms of nanozymes, their applications in treating various metabolic diseases, and the challenges and prospects for their application. 1. **Design of Enzyme-like Activity:** Nanozymes can exhibit various enzyme-like activities, such as oxidoreductase, hydrolase, lyase, and isomerase-like activities. These activities can be tailored to enhance catalytic efficiency and target specific diseases. 2. **Material Selection:** The choice of nanomaterials, such as metal nanoparticles, metal oxides, carbon-based materials, and metal-organic frameworks (MOFs), is crucial for achieving desired catalytic activities. 3. **Surface Functionalization:** Surface functionalization enhances the catalytic activity, stability, selectivity, and biocompatibility of nanozymes. Techniques such as attaching thiol groups, using biomolecules, and coating with polymer layers are commonly employed. 4. **Size and Shape Control:** The size and shape of nanozymes influence their performance in vivo. Smaller nanoparticles facilitate better tissue penetration but have shorter half-lives in the bloodstream. 5**Abstract:** Nanozymes, characterized by their enzyme-mimicking properties, have emerged as promising alternatives to natural enzymes due to their exceptional attributes such as regulation of oxidative stress, convenient storage, adjustable catalytic activities, remarkable stability, and scalability for large-scale production. Given the potent regulatory function of nanozymes on oxidative stress and the role of reactive oxygen species (ROS) in metabolic diseases, nanozymes offer a unique perspective for therapy through multifunctional activities, achieving essential results in the treatment of metabolic diseases by directly scavenging excess ROS or regulating pathologically related molecules. This review discusses rational design strategies, nanozyme-enabled therapeutic mechanisms at the cellular level, and the application of nanozymes in treating several typical metabolic diseases, including obesity, diabetes, cardiovascular disease, and diabetic wound healing. Additionally, the pharmacokinetics, safety analysis, challenges, and outlooks for the application of nanozyme are presented. **Keywords:** Nanozyme, Metabolic disease, Inflammation, Oxidative stress, Glucose homeostasis Nanozymes, characterized by high catalytic efficiency, stability, cost-effectiveness, and scalability, have found widespread applications in various fields. The concept of nanozymes was first proposed in 2004 and has since been extensively studied for their enzyme-like activities. Metabolic diseases, such as obesity, diabetes, and cardiovascular disorders, pose significant global health challenges. These diseases are characterized by impaired metabolic processes, including increased body weight, blood glucose, insulin resistance, inflammation, and oxidative stress. Traditional approaches to managing these diseases have limitations in terms of safety and efficacy, highlighting the need for innovative strategies. Nanozymes offer several advantages over traditional methods, including tunable properties, biocompatibility, biodegradability, targeted drug delivery, and cost-effective production. This review focuses on the rational design strategies and cellular-level mechanisms of nanozymes, their applications in treating various metabolic diseases, and the challenges and prospects for their application. 1. **Design of Enzyme-like Activity:** Nanozymes can exhibit various enzyme-like activities, such as oxidoreductase, hydrolase, lyase, and isomerase-like activities. These activities can be tailored to enhance catalytic efficiency and target specific diseases. 2. **Material Selection:** The choice of nanomaterials, such as metal nanoparticles, metal oxides, carbon-based materials, and metal-organic frameworks (MOFs), is crucial for achieving desired catalytic activities. 3. **Surface Functionalization:** Surface functionalization enhances the catalytic activity, stability, selectivity, and biocompatibility of nanozymes. Techniques such as attaching thiol groups, using biomolecules, and coating with polymer layers are commonly employed. 4. **Size and Shape Control:** The size and shape of nanozymes influence their performance in vivo. Smaller nanoparticles facilitate better tissue penetration but have shorter half-lives in the bloodstream. 5