Abstract: Serpentine is a magnesium silicate gangue mineral widely distributed in metallic deposits such as nickel sulfide ores and copper sulfide ores. Its distinctive layered crystal structure renders it prone to slime formation. Unsaturated positive surface charges originating from broken bonds of surface magnesium ions enable serpentine to non−selectively adsorb onto target mineral surfaces via heterocoagulation during grinding and flotation systems, forming dense slime coatings and severely deteriorating flotation separation efficiency. Based on crystal chemistry and surface electrochemistry, this paper systematically analyzes the microscopic mechanism by which serpentine interferes with flotation. It reviews research progress on inorganic depressants (silicates, phosphates, etc.), organic depressants (small−molecule organic depressants, natural polymers and synthetic polymers), and combined depressants, and thoroughly discusses the action pathways and synergistic mechanisms of various depressants. In view of current research bottlenecks and industrial demands, this work identifies molecular dynamics simulations considering crystal anisotropy, development of salt−tolerant green reagents, and integrated physical–chemical regulation technologies as key breakthrough directions for future research. It provides theoretical references and technical support for optimizing flotation separation technologies for complex serpentine−bearing sulfide ores and developing high−efficiency depressants.