To improve oral bioavailability of bioactive compounds, nano-scopic carrier systems with multiple layers has become the recent popular trend. The preparation of the nano-sized bilayer system usually requires multiple operations and intense energy input. For better efficiency, co-axial electrospraying was developed as the novel method to manufacture dual-layered nanocarrier. To improve the versatility of the production, the co-axial electrospray process was further guided by CCD-RSM (Central Composite Design-Response Surface Methodology) when generating bilayer nanocarrier. Chitosan and alginate were arranged into the core and shell part of the carrier, respectively. Through the RSM analysis, the optimum processing parameters to prepare the chitosan/alginate bilayer carrier with 112.1 ± 35.2 nm diameter were determined. The surface morphology and dual layer structure were characterized microscopically. In summary, this work has successfully developed a novel and versatile mean to efficiently produce bilayer nanocarrier using co-axial electrospray combine with CCD-RSM analysis. These results could serve as a firm foundation to promote electrospray technique for the preparation of oral carrier system containing bioactive components.