Flotation reagents are significant for modifying the interfacial characteristics of mineral grains to achieve the effective separation of minerals. Since the 1960s, when quantum chemistry was first introduced into the study of flotation reagents, many achievements have been made, although some controversial topics remain. The application of quantum chemistry in the research of flotation reagents for the separation of various minerals in the past decade is herein comprehensively and systematically reviewed. The main directions and gaps of current research are pointed out, the theoretical basis for the design and development of novel flotation reagents is summarized, and more importantly, the potential for the targeting design and development of efficient, selective, and environmentally friendly flotation reagent molecules by means of quantum chemistry is explored.