The equilibrium solubilities of the anti-inflammatory drug naproxen (NPX) in 2-propanol + water mixtures were determined at several temperatures from 298.15 to 313.15 K. The Gibbs energy, enthalpy, and entropy of solution and of mixing were obtained from these solubility data. The solubility was maximal in φ1 = 0.90 and very low in pure water at all the temperatures studied. A non-linear plot of ∆solnH° vs. ∆solnG° with negative slope from pure water up to 0.20 in volume fraction of 2-propanol and positive beyond this composition up pure 2-propanol was obtained at the mean temperature, 305.55 K. Accordingly, the driving mechanism for NPX solubility in the water-rich mixtures was the entropy, probably due to water-structure loss around non-polar moieties of the drug and for the 2-propanol-rich mixtures it was the enthalpy, probably due to its better solvation of the drug.