The aim of this present study was to investigate the structural-activity differences of polyester/polycarbonate nanofibers prepared via emulsion-electrospinning method. Poly(epsilon-caprolactone) (PCL) and poly(butylene carbonate) (PBC) were used as representative polymers and vancomycin hydrochloride (VCN) as a model compound in this study. The two kinds of nanofibers were compared in respect to their physical characteristics, such as water contact angle, fiber morphology and chemical degradation/release kinetics. Both FESEM and CLSM results showed uniform fiber morphology for the PCL/PBC nanofibers and the VCN was homogeneously distributed in the two fibers. The FTIR confirmed that hydrogen bonds existed between the VCN and PCL/PBC mats, while the water contact angle test showed the PBC nanofibers displayed a more hydrophilic surface, meaning the fiber surface contacted more surrounding water and thus accelerating its degradation rates in all pH media, especially the alkaline medium. The in vitro drug release tests showed that the PCL/PBC nanofibers exhibited similar release behaviors in acidic and physiological conditions, controlled by drug diffusion mechanism. The drug diffusion/polymer degradation-combined mechanism determined drug release profiles in alkaline environment and the PBC nanofibers displayed faster release rate in sustained periods.