Abstract The solubilities of the analgesic drug meloxicam (MEL) in ethanol + water cosolvent mixtures were determined at several temperatures from 293.15 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 0.85 mass fraction of ethanol at several temperatures and very low in pure water at all the temperatures studied. A non-linear plot of Δ H soln 0 vs. Δ G soln 0 with negative slope from pure water up to 0.85 mass fraction of ethanol and positive beyond this composition up to neat ethanol was obtained. Accordingly, the driving mechanism for MEL solubility in almost all mixtures is the entropy, probably due to water-structure loss around the drug non-polar moieties caused by the ethanol. The preferential solvation of MEL by the components of the solvent was estimated by means of the quasi-lattice quasi-chemical and by the inverse Kirkwood–Buff integral method, showing the preferential solvation of MEL by ethanol except at very low water contents, where water preferentially solvates the drug.