The solubilities of genistin in the binary solvent mixtures ethanol + water and acetone + water with various initial mole fractions were measured by high-performance liquid chromatography (HPLC) at different temperatures ranging from 278.2 to 313.2 K. An interesting phenomenon was observed, namely, a synergistic effect of the binary solvent mixtures on solubility. In this synergistic effect, the solubility of genistin reached a maximum and was higher than its solubility in the separate solvents when the initial mole fraction of ethanol or acetone was 0.5 throughout the whole range of temperatures studied. The solubility of genistin in the mixtures increased with temperature. A simplified thermodynamic model, the modified Apelblat model, and the a model were used to correlate the solubility data of genistin with temperature. Among the three models, the modified Apelblat model showed the best correlation in describing the dependence of the solubility on temperature. Furthermore, to illustrate the effects of both the temperature and the initial mass fraction of ethanol or acetone on the changes in the solubility of genistin, nonrandom two-liquid (NRTL), Sun, and Ma models were also used to correlate the data. The results showed that the solubilities calculated by the Sun model showed better agreement with the experimental data than those calculated by the other two models.