Temperature-dependent solubility data for mesalazine in the binary system of polyethylene glycol 400 (PEG 400)/water are determined by a shake-flask method at 293.2–313.2 K. The solubility data are validated to five different computational models including the van't Hoff, the mixture response surface, the Yalkowsky, the Jouyban-Acree, and the Jouyban-Acree-van't Hoff. All the investigated models have good correlation and validation according to obtained the mean relative deviations (MRD%) for back-calculated data. Moreover, apparent thermodynamic analysis shows an endothermic process for mesalazine in (PEG 400 + water) mixtures. Further, based on inverse Kirkwood-Buff integrals is observed that mesalazine is preferentially solvated by PEG in all the mixtures.