Experimental solubility data of cloxacillin benzathine in pure solvents and binary solvent mixtures from 278.15 to 313.15 K were measured using a multiple reactor setup. The measured data in pure solvents were correlated by the van't Hoff equation, modified Apelblat equation, lambda h equation, Wilson model, and NRTL model, and the Wilson model showed the best agreement. Thus, the activity coefficients of cloxacillin benzathine as well as the mixing Gibbs free energies, enthalpies, and entropies of the solutions were predicted with the correlation of experimental data based on the Wilson model. Some other properties were also estimated, including the infinite-dilution activity coefficients and excess enthalpies in pure solvents. The solubility data in binary solvent mixtures as a function of solvent composition were correlated by the Wilson model. The negative values of the calculated partial molar Gibbs free energies indicated the variation trend of the solubility.