RSM methodology was applied to present mathematical models for the fabrication of polyvinylidene fluoride (PVDF) dual-layer hollow fibers in membrane distillation process. The design of experiments was used to investigate three main parameters in terms of polymer concentration in both outer and inner layers and the flow rate of dope solutions by the Box-Behnken method. According to obtained results, the optimization was done to present the proper membrane with desirable properties. The characteristics of the optimized membrane (named HF-O) suggested by the Box-Behnken (at the predicted point) showed that the proposed models are strongly valid. Then, a morphology study was done to modify the fiber by a combination of three types of a structure such as macro-void, sponge-like and sharp finger-like. It also improved the hydrophobicity of outer surface from 87 to 113° and the mean pore size of the inner surface from 108.12 to 560.14 nm. The DCMD flux of modified fiber (named HF-M) enhanced 62% more than HF-O when it was fabricated by considering both of RSM and morphology study results. Finally, HF-M was conducted for long-term desalination process up to 100 hr and showed stable flux and wetting resistance during the test. These stepwise approaches are proposed to easily predict the main properties of PVDF dual-layer hollow fibers by valid models and to effectively modify its structure.