Abstract: Strategic mineral resources play an irreplaceable role in supporting national energy security and ensuring the stability of key industries. Currently, China faces the dual challenges of high consumption of bulk minerals and a surge in demand for emerging minerals, urgently requiring improvements in the utilization efficiency and separation precision of strategic mineral resources. Flotation, as an important physicochemical separation method, is widely applied in the beneficiation and enrichment of strategic minerals. As the core means of modifying mineral surfaces, flotation reagents directly determine flotation efficiency and product quality. The research progress and future trends of flotation reagents for strategic minerals in terms of molecular design and functional enhancement are systematically reviewed, with a focus on the four key attributes of “targeted, intelligent, green, and efficient.” In the aspect of “targeted”, research concentrates on the interfacial interaction mechanisms between reagents and mineral surfaces. Through single-molecule force spectroscopy and molecular docking methods, precise recognition and selective adsorption of reagents on target mineral surfaces are achieved. In the aspect of “intelligent”, modern technologies such as quantum chemical calculations, machine learning are used to construct the mapping relationship between reagent structure and performance, breaking the limitations of traditional empirical and trial-and-error methods, enabling high-throughput screening and performance prediction, and significantly improving development efficiency. In the aspect of “green”, attention is given to the environmental friendliness and sustainability of reagents, with research progress in developing green collectors through molecular structure optimization, biomass-based material substitution, and resource recycling. This not only reduces toxicity risks to the environment and human health but also reflects the transition of mineral resource development towards green and low-carbon approaches. In the aspect of “efficient”, the application of novel multifunctional reagents in complex systems is reviewed, which significantly outperform traditional reagents in terms of selectivity and collecting ability, while also achieving low dosage and low cost, thus realizing high performance and high economic efficiency in flotation processes. Future research on flotation reagents should focus on building a multi-dimensional data-driven design system, integrating molecular simulation, artificial intelligence, and green technologies to achieve a closed-loop process of “targeted recognition-intelligent prediction-green synthesis-efficient application.”