Drug distribution within its carrier in a solid dosage form often generates a profound influence on its release profile, particularly when the physicochemical properties of the carrier are exploited to manipulate drug release behavior. In this job, two different types of distributions of a model drug ibuprofen (IBU) within a protein gliadin in their electrospun nanofibers were intentionally created. One was homogeneous distribution in the monolithic fibers fabricated using a modified coaxial process, and the other one was heterogeneous distribution in the core/shell fibers prepared through a traditional coaxial process. SEM observations clearly demonstrated the different distributions of IBU within gliadin in the two kinds of nanofibers although both of them had smooth surfaces and linear morphology. XRD results showed that IBU was amorphously distributed in the monolithic fibers, but that some IBU crystalline lattices presented in the core/shell fibers. FTIR and RM spectra suggested that gliadin had good compatibility with IBU. In vitro dissolution tests verified that the gliadin nanofibers with a heterogeneous drug distribution could provide a better sustained release profile than its counterpart in terms of initial burst release and sustained release time period. Both the fiber formation and drug-controlled release mechanisms are suggested. The present study demonstrated a concept that drug distribution with the medicated nanomaterials can be exploited as a tool to optimize the drug sustained release profile.