Abstract: The flotation of complex solid–liquid multiphase systems involve interactions among multiple components, the core problem facing flotation theory. Meanwhile, the combined use of multicomponent flotation reagents to improve mineral flotation has become an important issue in studies on the efficient use of refractory mineral resources. However, studying the flotation of complex solid–liquid systems is extremely difficult, and no systematic theory has been developed to date. In addition, the physical mechanism associated with combining reagents to improve the flotation effect has not been unified, which limits the development of flotation theory and the progress of flotation technology. In this study, we applied theoretical thermodynamics to a solid–liquid flotation system and used changes in the entropy and Gibbs free energy of the reagents adsorbed on the mineral surface to establish thermodynamic equilibrium equations that describe interactions among various material components while also introducing adsorption equilibrium constants for the flotation reagents adsorbed on the mineral surface. The homogenization effect on the mineral surface in pulp solution was determined using the chemical potentials of the material components of the various mineral surfaces required to maintain balance. The flotation effect can be improved through synergy among multicomponent flotation reagents; its physical essence is the thermodynamic law that as the number of components of flotation reagents on the mineral surface increases, the surface adsorption entropy change increases, and the Gibbs free energy change of adsorption decreases. According to the results obtained using flotation thermodynamics theory, we established high-entropy flotation theory and a technical method in which increasing the types of flotation reagents adsorbed on the mineral surface, increasing the adsorption entropy change of the flotation reagents, decreasing the Gibbs free energy change, and improving the adsorption efficiency and stability of the flotation reagents improves refractory mineral flotation.