Ketoprofen (KTP) is an anti-inflammatory drug widely used in therapeutics. By using the van't Hoff and Gibbs equations, the thermodynamic functions Gibbs energy, enthalpy, and entropy of solution and mixing for KTP in ethanol (EtOH) + water cosolvent mixtures were evaluated from solubility data determined at several temperatures. The solubility was greater in pure EtOH and lower in water at all temperatures studied. This behavior shows the cosolvent effect present in this system. By means of enthalpy−entropy compensation analysis, a nonlinear ΔsolnH0 vs ΔsolnG0 plot with negative slope from pure water up to 0.6 in mass fraction of EtOH and positive beyond this EtOH proportion was obtained. Accordingly to this result, it follows that the dominant mechanism for solubility of KTP in water-rich mixtures is the entropy, probably due to water-structure loosening around the drug nonpolar moieties by EtOH, whereas over 0.6 in mass fraction of EtOH, the dominant mechanism is the enthalpy probably due to the KTP solvation increase by EtOH molecules.