Collagen was extracted from abandoned Rana chensinensis skin in northeastern China via an acid enzymatic extraction method for the use of drug carriers. In this paper we demonstrated two different nanofiber-vancomycin (VCM) systems, that is, VCM blended nanofibers and core-shell nanofibers with VCM in the core. Rana chensinensis skin collagen (RCSC) and poly(L-lactide) (PLLA) (3 : 7) were blended in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) at a concentration of 10% (g/mL) to fabricate coaxial and blend nanofibers, respectively. Coaxial and blend electrospun RCSC/PLLA nanofibers containing VCM (5 wt%) were evaluated for the local and temporal delivery of VCM. The nanofiber scaffolds were characterized by environmental scanning electron microscope (ESEM), transmission electron microscopy (TEM), Fourier transform infrared spectra (FTIR), differential scanning calorimeter (DSC), water contact angle (WCA), and mechanical tests. The drug release of VCM in these two systems was compared by using UV spectrophotometer. The empirical result indicated that both the blend and coaxial RCSC/PLLA scaffolds followed sustained control release for a period of 80 hours, but the coaxial nanofiber might be a potential drug delivery material for its better mechanical properties and sustained release effect.