The solubilisation behaviour of ketoconazole in the binary mixtures of acetonitrile and water was studied at T = (293.2–313.2) K. The solubility data were represented with seven co-solvency models including Jouyban-Acree, Jouyban-Acree-van't Hoff, NRTL, Wilson, UNIQUAC, combined nearly ideal binary solvent/Redlich-Kister and modified Wilson models. The computed thermodynamic properties of dissolution suggest that except in neat water, the main contributor to standard Gibbs free energies of dissolution is enthalpy. Furthermore, preferential solvation analysis shows that ketoconazole is preferentially solvated by water in water-rich mixtures and also in acetonitrile-rich mixtures but preferentially solvated by acetonitrile in mixtures of intermediate compositions.