Protein-protected metal nanoclusters (MNCs), typically consisting of several to a hundred metal atoms with a protein outer layer used for protecting clusters from aggregation, are excellent fluorescent labels for biomedical applications due to their extraordinary photoluminescence, facile synthesis and good biocompatibility. Interestingly, many protein-protected MNCs have also been reported to exhibit intrinsic enzyme-like activities, namely peroxidase, oxidase and catalase activities, and are consequently used for biological analysis and environmental treatment. These findings have extended the horizon of protein-protected MNCs' properties as well as their application in various fields. Furthermore, in the field of nanozymes, protein-protected MNCs have emerged as an outstanding new addition. Due to their ultra-small size (<2 nm), they usually have higher catalytic activity, more suitable size for in vivo application, better biocompatibility and photoluminescence in comparison with large size nanozymes. In this review, we will systematically introduce the significant advances in this field and critically discuss the challenges that lie ahead. Ultra-small nanozymes based on protein-protected MNCs are on the verge of attracting great interest across various disciplines and will stimulate research in the fields of nanotechnology and biology. This article is characterized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Protein and Virus-Based Structures.