The main aim of the present study was to electrospin ibuprofen (IBU)-loaded composite nanofibers to improve the performances of transdermal patches. Cellulose acetate/poly(vinyl pyrrolidone) (CA/PVP) blends were used to fabricate uniform nanofibers. Investigations on the physicochemical properties of CA/PVP solutions indicated that the addition of appropriate PVP improved the electrospinnability of original CA solutions. Detections on the physical states of IBU in medicated CA/PVP nanofibers suggested that IBU was uniformly distributed in nanofibers in an amorphous state. Comparing to IBU-loaded casting membrane, the medicated CA/PVP nanofibers provided a faster IBU diffusion manner and a better ex vitro skin permeation profile due to their high superficial areas and the amorphous IBU. Furthermore, CA/PVP nanofibers exhibited a high water vapor permeability, which could render an improved breathability to transdermal patches. In sum, the electrospun drug-loaded CA/PVP nanofibers exhibited great potentials to improve the thermodynamic stability and breathability of transdermal patches, which could be used to develop new types of transdermal drug delivery system (TDDS).