By means of a shake-flask method, the measurement of equilibrium diphenoxylate solubility in aqueous solutions comprising one of the solvents of ethanol, acetonitrile, methanol, and isopropanol was performed at a local pressure of 101.2 kPa and temperatures from 278.15 to 318.15 K. The mole fraction solubility of diphenoxylate was higher in methanol + water mixture than in isopropanol + water, acetonitrile + water, and ethanol + water mixtures under the conditions of the same mass fractions of ethanol (acetonitrile, methanol, or isopropanol) and temperatures. The relative prominence of solvent-solvent and solute-solvent interactions on diphenoxylate solubility variation was inspected by the linear solvation energy relationship analyses of the solvent effect. The preferential solvation pertaining to thermodynamic solution properties was studied through the inverse Kirkwood-Buff integral method. The parameters of the preferential solvation of ethanol, acetonitrile, methanol, and isopropanol were positive in the studied mixtures within the cosolvent-rich and intermediate compositions, indicating the preferential solvation of diphenoxylate by the cosolvents. In addition, the drug solubility was represented mathematically using the Jouyban-Acree model and the van't Hoff-Jouyban-Acree model, yielding the average relative deviations no higher than 4.58%.