In this study, four model drugs, i.e., Meloxicam (MEL), Risperidone (RIS), Eprinomectin (EPR), and Bull Serum Albumin (BSA), were encapsulated in PLGA microspheres via solvent evaporation methods. The encapsulation efficiency and in vitro release profiles of different drugs with various water solubilities from medicated PLGA microspheres were investigated. The surface morphologies of microspheres were detected by scanning electron microscope (SEM). The release characteristics of the model drugs from the medicated microspheres were carried out in the phosphate buffer solution (PBS), pH7.4, at 37 °C. Studies found that the water solubility of model drugs had significant influences on their in vitro release profiles and the release rates of four model drugs were in the orders of BSA>MEL>RIS>EPR.