The equilibrium solubility of sulfadiazine (SD, 3) in {acetonitrile (MeCN, 1) + methanol (MeOH, 2)} mixtures at nine temperatures from 278.15 K to 318.15 K has been determined and correlated by means of some well-known thermodynamic correlation models. Five models including van't Hoff, the mixture response surface (MRS), Jouyban-Acree, Jouyban-Acree-van't Hoff and the modified Wilson models were applied to mathematical solubility data modelling. The accuracy of each model is investigated by the mean relative deviations (MRD%) of the back-calculated solubility. All used models show a low MRD% values (< 8.0%) for the calculated data indicating a good correlation of sulfadiazine solubility data with the given mathematical models. By using the van't Hoff and Gibbs equations the respective apparent thermodynamic quantities of the dissolution and mixing processes, namely Gibbs energy, enthalpy, and entropy, were calculated. Non-linear enthalpy–entropy relationship was observed for SD in the plot of enthalpy vs. Gibbs energy exhibiting negative slope in the composition region 0.00 < w1 < 0.05 indicating entropy-driving mechanism for this transfer process, and variant but mainly positive slopes in the composition interval 0.05 < w1 < 0.30, indicating enthalpy-driving mechanism for these transfer processes. From w1 = 0.30 to neat MeCN a slope near zero is observed. Furthermore, the preferential solvation of SD by MeCN or MeOH was analysed by using the inverse Kirkwood-Buff integrals. Thus, SD is preferentially solvated by MeOH molecules in MeOH-rich mixtures.