Background <p>Immune-mediated inflammatory diseases (IMIDs) are chronic disorders involving multiple organs and driven by shared pathogenic pathways. Current therapeutic approaches, such as disease-modifying anti-rheumatic drugs (DMARDs) and biologics, are limited by infection risks, poor tissue specificity, and suboptimal long-term efficacy, underscoring the need for novel therapies. Nanozymes, nanomaterials with enzymatic activities, have garnered considerable interest for treating IMIDs due to their potential to counteract oxidative stress. Nevertheless, a systematic assessment of their therapeutic applications, mechanisms, and clinical translation challenges in IMIDs remains lacking.</p> Findings <p>Given the critical pathogenic role of reactive oxygen species (ROS) in IMIDs, nanozymes, particularly those with oxidoreductase activity, have demonstrated significant therapeutic potential. They modulate ROS levels, restore immune homeostasis, and remodel the local inflammatory microenvironment, either as monotherapy or in combination with conventional agents. To overcome challenges such as biosafety, off-target effects, and clinical translatability, strategies successfully explored in other diseases, such as biodegradable or organic–inorganic hybrid nanozymes, pH-responsive targeting designs, erythrocyte membrane coatings, and ROS-responsive carriers, may be adapted to enhance tissue specificity and safety in IMID treatment. Further investigation is warranted to adapt and optimize these strategies for effective and safe nanozyme-based therapy in IMIDs.</p> Conclusion <p>This review synthesizes current evidence to summarize the therapeutic potential and underlying mechanisms of nanozymes in IMIDs, while highlighting key challenges and future directions to guide the development and clinical translation of nanozyme-based therapies.</p>