ABSTRACTThe purpose of this study was to compare the degradation and release behaviors of poly(lactide‐co‐glycolide) (PLGA)–methoxypoly(ethylene glycol) microspheres fabricated by the single‐emulsion evaporation method (DEEM) and double‐emulsion evaporation methods (DEEM). Vancomycin and mizolastine were used as the hydrophilic and hydrophobic model drugs, and they were encapsulated into microspheres through DEEM and SEEM, respectively. The two types of microspheres were similar in size distribution, but the mizolastine‐loaded microspheres showed a much higher encapsulation efficiency than those loaded with vancomycin. Scanning electron microscopy, size, and molecular weight (Mw) analyses during the degradation revealed that the microspheres fabricated by DEEM underwent a bulk degradation process and showed a faster MW reduction rate during the early degradation period than the microspheres fabricated by SEEM, which exhibited a surface‐to‐bulk degradation process according to the Mw and morphological changes. The mass loss rates of the two types of microspheres were similar, but the mean size decrease rates showed a little difference. The mizolastine‐loaded microspheres exhibited an approximately linear release profile after the initial burst release, whereas the vancomycin‐loaded microspheres showed a more severe burst release, a faster release rate, and thus, a shorter time to full release. © 2015 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2015, 132, 41943.