The present paper describes the structural design and fabrication of silk fibroin (SF)/polyester (PET)-based bifurcated stent-graft (BSG) using orthogonal experimental design (OED) and range analysis (RA). An orthogonal design comprising of three factors was used, including basic weave, warp × weft density and warp × weft materials, each factor contains three different levels. As a result, nine kinds of BSGs with different weaves, densities and materials were prepared using a modified rigid rapier weaving loom. Water permeability and wall thickness were evaluated according to standard protocols (ISO 7198:2016). Furthermore, weaving process was optimized and RA was used to detect how performance was affected by factors. The results showed that the thickness of almost all samples is near or less than 0.1 mm, which is required for BSG used in endovascular graft exclusion. Whereas, the water permeability is with a large variation compared to thickness, because BSGs made of pure SF possess significant lower water permeability than that made of pure PET or SF-PET mixed. The water permeability of sample g is only 5.19 ml/ (cm2 × min), which can prevent blood leakage after transplantation according to the standard. In conclusion, the SF-based BSG has better performance in terms of water permeability, which is more suitable as BSG used in endovascular exclusion.