Volumetric muscle loss (VML) results in the impediment of skeletal muscle function. Tissue engineering scaffolds have been widely developed and used in skeletal muscle regeneration. However, scaffold implantation causes an immune response that endogenously regulates implant integration and tissue regeneration. Moreover, vascularization is thought to be a principal obstacle in the reconstruction of skeletal muscle defects. Thus, creating a pro-regenerative microenvironment that facilitates muscle regeneration and supports angiogenesis represents a promising strategy for tissue repair following volumetric muscle loss (VML) injury. Previously, the electrospun silk fibroin-silk sericin (SF-SS) film could regulate macrophage polarization and promote neovessel formation. This study aimed to investigate if the electrospun SF-SS scaffold was capable of supporting functional muscle regeneration. The results indicate that the conditioned medium collected from macrophages co-cultured with the 7:3 SF-SS scaffold significantly enhanced the proliferation and migration of myoblast C2C12 cells and improved the tube formation of HUVECs. Data from animal studies showed that the 7:3 SF-SS scaffold significantly enhanced M2 macrophage polarization, vascularization, and muscle fiber regeneration, reduced fibrosis, and improved muscle function after VML injury, thereby promoting the repair of muscle tissue. Therefore, the 7:3 SF-SS scaffold might represent a potential candidate for skeletal muscle regeneration following VML injury.