Silk fibroin (SF) is a widely explored biopolymer for wound-healing applications due to the presence of amino acids in the biodegradable polymer chain with superior mechanical properties. Herein, a high SF-loaded fibrous matrix along with poly(ε-caprolactone) (PCL) was fabricated using electrospinning of emulsion and blend compositions to modulate nanostructure morphology. A comparative study of the physicomechanical properties of electrospun fibers with emulsion (eS7P3) and homogenous blend (bS7P3) was performed as well. In both compositions, SF loading of up to 70% was successfully achieved in the spun fibers while emulsion yielded core-shell morphology, and the blend resulted in monolith fiber architecture as evidenced by TEM microscopy. Further characterization revealed superior mechanical properties in S7P3 fiber with core-shell morphology, as compared to those in the monolith in terms of a higher degree of crystallinity with Young's modulus of 60 MPa under tensile test and nanoindentation modulus of 1.59 ± 0.8 GPa. Further, eS7P3 nanostructure morphology containing silk in the core with a thin outer layer of PCL facilitated relatively faster biodegradation in the lysozyme medium, as compared to that in the monolith. Owing to the presence of a hydrophobic shell, protein adsorption on the fibrous mat presented slow but steady kinetics up to 24 h. When the scaffold was seeded with human placenta-derived mesenchymal stem cells (hPMSCs), in vitro study confirmed that the eS7P3 structure had marginally higher cell proliferation with superior cell infiltration than the monolith. Further, in vivo study involving a rodent model showed the potential of the eS7P3 fiber substrate with a core-shell structure for accelerating full-thickness wound healing by inducing hair follicle and wound closure with less scar formation after 15 days.