Electrospinning is an effective and common method utilized to produce fibers from sub-micrometer to nanoscale. Although poly(vinyl alcohol) (PVA) can be easily electrospun in water, its widespread usage limited in electrospinning applications due to its poor solubility in organic solvents. In this regard, this study concentrated on partially modifying of PVA via chemical transformation by treating with dichloroacetic acid (DCAA) (poly(VA-co-VDCAc)) and triethyl amine (TEA) (poly(VA-co-VDCAc-co-QVAc)), respectively to increase organosolubility as well as provide antibacterial activity. Additionally, the modal drug, namely naproxen sodium (NAP), was incorporated into the modified polymer matrixes by simple blending. Electrospinning method was applied to fabricate the organosoluble, quaternized and NAP-loaded PVA-based nanofibers as potential drug carriers in controlled drug release. The chemical structure, morphology, wettability as well as the thermal features of the obtained nanofibers and their precursors at various stages were investigated using Fourier-transform infrared (FT-IR), proton nuclear magnetic resonance (1H NMR) spectroscopies, scanning electron microscopy (SEM), water contact angle (WCA) measurements, thermogravimetric and differential scanning calorimetry (TGA and DSC) analyses, respectively. SEM images proved that the nanofibers had noticeably smooth, cylindrical, uniform, and continuous and the modification reactions were affected the mean diameter of the samples. The utilization of modified electrospun PVA-based nanofibers as carrier for delivery of naproxen sodium (NAP) was elucidated. Release behaviors of the electrospun fibers were determined at pH 7.4, and the release of the NAP was faster for non-quaternized sample. Antibacterial activity of electrospun nanofibers against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) bacteria was evaluated in vitro, and poly(VA-co-VDCAc-co-QVAc)s electrospun nanofibers have better potential in killing bacteria. Overall, this research provides useful guidance for tailoring electrospinning processes for drug delivery of PVA-based materials.