A novel seamless silk fibroin-based endovascular prosthesis (SFEPs) with bifurcated woven structure and anticoagulant function for the improvement of patency is described. The SFEPs were prepared from silk fibroin (SF) and polyester filaments using an installed weaving machine. The production processing parameters were optimized using orthogonal design methods. The inner surface of SFEPs was modified with polyethylenimine (PEI) and EDC/NHS-activated low-molecular-weight heparin (LMWH) to enhance anticoagulant function. The surface morphology and mechanical properties of the SFEPs were evaluated according to standard protocols. The thickness of modified SFEPs was lower than 0.085 ± 0.004 mm and water permeability was lower than 5.19 ± 0.30 mL/(cm2 × min). The results of mechanical properties showed that the diametral tensile strength and burst strength reached 61.6 ± 1.8 and 23.7 ± 2.2 MPa, respectively. Automatic coagulometer and energy-dispersive X-ray (EDX) confirmed LMWH immobilization on the surface of the SFEPs and the blood compatibility was improved with the heparin modification with PEI polymerization. In conclusion, the new prosthesis has potential applications in the blood vessel repairs where minimal thickness but superior mechanical strength and biocompatibility are important.