The solubility data of diphenoxylate in pure solvents of water, methanol, ethanol, acetone, acetonitrile, 2-propanol were measured within the temperature range of 293.15-318.15 K by a static analytical method under atmospheric pressure. Several commonly used thermodynamic models, including the ideal solution model, the modified Apelblat equation and the Buchowski-Ksiazaczak lambda h equation, were applied to correlate the experimental solubility data. The experimental results show that the solubility increases with the increasing temperature, and the highest solubility is in methanol, the lowest in pure water. Results of these measurements were well-correlated with the three equations above, but the modified Apelblat equation is more suitable in regressing the solubility data of diphenoxylate. Through the Vant Hoff equation, the enthalpy and the entropy in different solvents can be calculated.