This study reports the experimental mesalazine solubility data in the binary mixtures of ethanol and water at temperature ranges of 293.2–313.2 K. The generated data are correlated with six co-solvency mathematical models including the van't Hoff, the mixture response surface, the Yalkowsky, the Jouyban–Acree, the Jouyban–Acree–van't Hoff, and the modified Wilson models, and the mean relative deviations (MRD%) of the back-calculated solubility for each investigated model are reported. Density of the mesalazine saturated solutions as another physicochemical property are also fitted by the Jouyban–Acree model. Moreover, standard enthalpy, entropy and Gibbs free energy changes for mesalazine dissolution process are obtained by using the van't Hoff and Gibbs equations. Furthermore, by means of inverse Kirkwood-Buff integrals is observed that mesalazine is preferentially solvated by water in almost all the mixtures studied.