Abstract: Mineral flotation separation relies on differences in the physicochemical properties of mineral surfaces. The core of the flotation process lies in the precise regulation of interactions at the gas-liquid-solid three-phase interface. Driven by rapid advancements in microscopic characterization techniques and theoretical simulation methods, an in-depth analysis of microscopic chemical mechanisms at flotation interfaces at the atomic and molecular levels is of profound theoretical and practical significance for overcoming separation bottlenecks of complex refractory ores and enhancing the comprehensive utilization efficiency of mineral resources. This paper systematically reviews the latest research progress in selective interfacial regulation technologies for mineral flotation. The focus is placed on the mineral-water and reagent-mineral interfaces. The underlying microscopic mechanisms are systematically elucidated. These include surface dissolution and reagent adsorption. Two mainstream interfacial regulation strategies are critically evaluated. These strategies are surface pretreatment and defect engineering. The evaluation encompasses chemical pretreatments such as sulfidation and oxidation, plasma modification, and ultrasound-assisted physical modification. It also covers defect engineering approaches. These approaches enable targeted control of surface vacancies, the proportions of exposed crystal facets, and surface roughness through chemical modification and adjustments to grinding processes. The intrinsic synergistic mechanism between selective grinding and flotation interfacial chemistry is revealed. The mechanisms underlying differential regulation of mineral surface physicochemical properties are analyzed in depth. This analysis considers galvanic corrosion effects, selective fracture behavior along crystal planes, and reagent addition timing. Key issues in current research are addressed. Future research should focus on refining the multiscale theoretical framework of interfacial chemistry, developing highly targeted flotation reagent molecules, and further investigating the coupling between selective grinding processes and interfacial regulation. These efforts aim to provide robust theoretical support for the efficient and environmentally friendly separation of complex strategic mineral resources.