In this study, propolis extract (PE) was first encapsulated in different liposomal formulations (65–370 nm) with high encapsulation efficiency (68%–93%). The liposomal PE was further embedded in a food-grade gelatin-zein core/shell fiber by using the co-axial electrospinning method. Transmission electron and confocal laser scanning microscopy verified the structure of liposomes and their homogeneous dispersion in fibers. Scanning electron microscopy (SEM) images confirmed the smooth morphologies of core/shell liposomal fibers. The loading of PE in liposomal fibers improved both thermal (differential scanning calorimetry) and textural (elongation at break and tensile strength) properties, and the fibers loaded with more PE provided higher mucoadhesiveness. The PE-loaded fiber showed higher antimicrobial activity against Staphylococcus aureus. The incorporation of liposomal PE in fiber enhanced the viability of human skin fibroblast (HFF-1) cells. The adhesion of HFF-1 cells on fiber was demonstrated by SEM, thus PE-loaded liposomal fiber could provide an efficient platform for cell growth. The findings of this study proposed that propolis-loaded liposomal hybrid fibers produced by the co-axial method can be used as a potential wound healing material.