Melanoma is the most aggressive type of skin cancer and has very high rates of mortality. The primary objective of this study was to fabricate core-shell nanofibers as a drug delivery system using the coaxial electrospinning technique, which provides some distinct features. Polycaprolactone (PCL)-chitosan (CS)/polyvinyl alcohol (PVA) core-shell nanofibers embedded with Pioglitazone hydrochloride-loaded Nanoemulsions (PIO NEs), a general anti-diabetic drug, and Gemcitabine hydrochloride (GEM), a chemotherapeutic agent, were prepared to investigate the effects of combination of GEM and PIO against A375 melanoma skin cancer cells in vitro. The prepared PCL-CS/PVA-PIO NEs-GEM core-shell nanofibers exhibited sustained and controlled release profiles of GEM and PIO NEs over 14 days, which was fitted into various kinetic models. The data demonstrated the efficacy of nanoemulsions in improving the solubility and release of the poorly aqueous soluble drug PIO. The maximum amount released from the core-shell nanofibers reached 76.99 ± 1.5% of the GEM and 80.47 ± 2.01% of the PIO in a medium of pH 7.4. The nanofibers' morphology, chemical composition, weight loss, and swelling behavior were evaluated. MTT and flow cytometry analyses demonstrated that the combination of PIO and GEM effectively inhibited the growth of melanoma cancer cell lines by inhibiting proliferation with cell viability of 47.07 ± 2.5%, 45.36 ± 2.8%, and 39.79 ± 1.8% after 24, 48 and 72 h, inducing G /G phase arrest and apoptosis, and exhibited an enhanced combinatorial effect in A375 cells in vitro. Additionally, real-time PCR analysis confirmed the induction of apoptosis by measuring gene expression levels, suggesting that the mechanism is associated with the P53 and PPARγ pathways. The generated core-shell nanofibers exhibit properties that suggest their potential as an innovative local drug delivery system, suitable for direct implantation at the tumor site for melanoma treatment through a unique combination therapy of PIO and GEM.