As the population ages, the number of vascular surgery procedures performed increases. Older adults often have multiple comorbidities, such as diabetes and hypertension, that increase the risk of complications from vascular surgery including vascular graft infection (VGI). VGI is a serious complication with significant morbidity, mortality, and healthcare costs. Here, we aimed to develop a nanofibrous chitosan-based coating for vascular grafts loaded with different concentrations of the vancomycin antibiotic vancomycin (VAN). Blending chitosan with poly(vinyl alcohol) or poly(ethylene oxide) copolymers improved solubility and ease of spinning. Thermal gravimetric analysis and Fourier transform infrared spectroscopy confirmed the presence of VAN in the nanofibrous membranes. Kinetics of VAN release from the nanofibrous mats were evaluated using high-performance liquid chromatography, showing a burst followed by sustained release over 24 h. To achieve longer sustained release, a poly(lactic--glycolic acid) coating was applied, resulting in extended release of up to 7 days. Biocompatibility assessment using human umbilical vein endothelial cells demonstrated successful attachment and viability of the nanofiber patches. Our study provides insights into the development of a drug delivery system for vascular grafts aimed at preventing infection during implantation, highlighting the potential of electrospinning as a promising technique in the field of vascular surgery.