The main aim of this study was to inhibit the re-crystallization of a potent antimalarial drug, artemisinin (ART), by encapsulating it in core-shell fibers via a coaxially electrospun method. The ART-infiltrated cellulose acetate (CA) solution as the core material and poly(vinyl pyrrolidone) (PVP) solution as the shell material were used to prepared ART-loaded core-shell fibers ([ART/CA]/PVP). Transmission electron microscopy images confirmed the core-shell structures of the coaxially electrospun fibers. The scanning electron microscope (SEM), X-ray diffraction, and differential scanning calorimetry were performed to characterize the physical states of ART in the fibers. It was observed that ART crystals were formed in the ART-loaded CA/PVP composite fibers (ART/CA/PVP) during the electrospinning process and increased during storage duration. While ART crystals hardly were observed in the fresh core-shell [ART/CA]/PVP fibers with high ART entrapped amount (20wt.%) and a little was detected after 6-month storage. Fourier transform infrared spectroscopy (FTIR) results illustrated the hydrogen bonding interaction between ART and CA in the core-shell [ART/CA]/PVP fibers mainly contributed to the amorphous state of ART. Importantly, combination of the hydrophilic PVP shell and the amorphous ART in CA core, the core-shell [ART/CA]/PVP fibers provided a continued and stable ART release manner. Ex vivo permeation studies suggested the amorphous ART in the medicated core-shell fibers could permeate through the stratum corneum smoothly. Hence, the core-shell [ART/CA]/PVP fiber matrix could provide a potential application in transdermal patches.