In this study, the solubility of cefathiamidine was measured in water + (acetone, ethanol, or 2-propanol) at temperature from (278.15 to 313.15) K by using a gravimeteic method. The solubility of cefathiamidine increased with increasing temperature. Besides, at a given temperature, solubility in different mixtures follows different rules. In water + (acetone or 2-propanol), it decreases with the increase of the initial molar fraction of acetone or 2-propanol; whereas synergistic effect of mixed solvents was observed in water + ethanol mixtures, and solubility reached maximum at the ethanol molar fraction of 0.4. The experimental data were well correlated by the modified Apelblat equation, the CNIBS/R-K model, the combined version of the Jouyban-Acree and vant Hoff model, and the combined version of the Jouyban-Acree and the modified Apelblat model. Furthermore, the thermodynamic functions of dissolution of cefathiamidine in different mixtures were obtained based on the van't Hoff equation and the modified Apelblat equation. The results indicate that the dissolution process of cefathiamidine is endothermic.