This study reveals the state-of-the-art fabrication of a tripolymer-based electrospun nanofiber (NF) system to enhance the release, solubility, and transdermal penetration of curcumin (Cur) with the aid of in situ release of infused castor oil (Co). In this regard, Cur-loaded Co-infused polyethylene oxide (PEO), ethyl cellulose (EC), and polyvinyl pyrrolidone (PVP) tripolymer-based NF systems were developed to produce a hybridized transdermal skin patch. Weight percentages of 1-4% Cur and 3-10% of Co were blended with PEO-EC-PEO and PEO-EC-PVP polymer systems. The prepared NFs were characterized by SEM, TEM, FT-IR analysis, PXRD, differential scanning calorimetry (DSC), and XPS. Dialysis membranes and vertical Franz diffusion cells were used to study the in vitro drug release and transdermal penetration, respectively. The results indicated that maintaining a Cur concentration of 1-3 wt % with 3 wt % Co in both PEO-EC-Co-Cur@PEO and PEO-EC-Co-Cur@PVP gave rise to nanofibers with lowered diameters (144.83 ± 48.05-209.26 ± 41.80 nm and 190.20 ± 59.42-404.59 ± 45.31 nm). Lowered crystallinity observed from the PXRD patterns and the disappearance of exothermic peaks corresponding to the melting point of Cur suggested the formation of an amorphous NF structure. Furthermore, the XPS data revealed that the Cur loading will possibly take place at the inner interface of PEO-EC-Co-PEO and PEO-EC-Co-PVP NFs rather than on the surface. The beneficiary role of Co on the release and dermal penetration of Cur was further confirmed from the respective release data which indicated that PEO-EC-Co-Cur@PEO would lead to a rapid release (4-5 h), while PEO-EC-Co-Cur@PVP would lead to a sustained release over a period of 24 h in the presence of Co. Transdermal penetration of the released Cur was further evidenced with the development of color in the receiver compartment of the diffusion cell. DPPH results further corroborated that a sustained antioxidant activity is observed in the released Cur where the free-radical scavenging activity is intact even after subjecting to an electrospinning process and under extreme freeze-thaw conditions.