The solubility of penicillin V potassium (PVK) in binary ethanol + water and 1-butyl alcohol + water solvent mixtures was measured at temperatures ranging from (278.15 to 313.15) K. The solubility in ethanol + water was measured by a static analytical method while in 1-butyl alcohol + water a dynamic method was adopted. It was found that the solubility of PVK increased with increasing temperature as well as the increase of the initial mole fraction of water. The modified Apelblat equation, the CNIBS/R-K equation, the combined version of the Jouyban-Acree and vant Hoff model, and the hybrid model were used to correlate the solubility data in ethanol + water solvent mixtures, among which the CNIBS/R-K equation gave the best correlation results. The experimental solubility data in 1-butyl alcohol + water were correlated well by the vant Hoff equation and the modified Apelblat equation. The dissolution enthalpy, entropy, and Gibbs energy of PVK in these solvent mixtures were obtained based on the vant Hoff equation.