The present study reports the fabrication of medicated nanofibers for potential colon-targeted drug delivery using modified coaxial electrospinning, in which salt (NaCl) solutions were exploited as shell fluids to facilitate the preparation processes. A homemade concentric spinneret with an indented core capillary was developed to conduct the coaxial processes. Optical observations and scanning electron microscopic results demonstrated that the shell-to-core fluid flow rate ratio was a key parameter, which exerted a significant influence on the electrospinning processes and could be exploited to control the fibers' morphology and diameters. A scaling law of D = 0.173F(-0.531) (R-2 = 0.9976) was built, by which the nanofibers' sizes can be predicted and manipulated easily. X-ray diffraction and attenuated total reflected FTIR tests verified that the medicated nanofibers were essentially a polymeric nanocomposite and the guest drug diclofenac sodium (DS) had fine compatibility with the host polymer. All the drug was encapsulated in the filament-forming carrier. In vitro dissolution experiments demonstrated that the medicated nanofibers could free the drug in a neutral condition, suggesting potential colon-targeted drug delivery applications. Ex vivo tests demonstrated that the medicated fiber mats could enhance the transmembrane of DS. Based on coaxial electrospinning, a new strategy is successfully developed for creating medicated nanomaterials.