Abstract The solubility of ketoconazole was measured in aqueous mixtures of 1,4-dioxane at T = (293.2 to 313.2) K using the shake flask method. To mathematically represent the generated solubility data, combined nearly ideal binary solvent/Redlich-Kister (CNIBS/R-K), van't Hoff, Jouyban-Acree, Jouyban-Acree-van't Hoff, UNIQUAC, and NRTL models were applied. Differences of experimental and predicted values were expressed as the percentage of averaged relative deviation (% ARD). Apparent thermodynamic quantities of ketoconazole dissolution and mixing were reported at harmonic temperature. Moreover, the dissolution mechanism of ketoconazole was studied in 1,4-dioxane + water mixtures. Based on the inverse Kirkwood-Buff integrals, the preferential solvation parameters were calculated and it is observed that ketoconazole is preferentially solvated by water in water-rich and 1,4-dioxane-rich mixtures.