The solubility of methylparaben was determined in acetonitrile + water mixtures at several temperatures (278.15 K to 318.15 K). The solubility curves as a function of acetonitrile ratio showed a maximum at a mass fraction of acetonitrile 0.85 at all temperatures. In all cases, the homogeneous mixture splits into two liquid immiscible phases. The concentration range at which phase separation takes place is 0.35–0.70 in a mass fraction of acetonitrile, showing a clearer separation at higher study temperatures. According to the results of DSC, this phase separation was not related to solid phase changes (polymorphism). The apparent enthalpy of the solution process was a nonlinear function of the acetonitrile ratio, and the solution process of the drug is endothermic and enthalpy determined. Finally, the enthalpy-entropy compensation analysis shows a non-linear behaviour, possibly due to the influence of acetonitrile in the solution process of methylparaben in cosolvent acetonitrile + water mixtures.