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Silk fibroin nanofibers find broader applications in skin tissue engineering as wound dressings. In this study, we have prepared biocompatible collagen-coated silk fibroin nanofibers with two small molecules: sinomenine hydrochloride (SH) and kaempferol hydrate (KH) with bioactive properties for wound healing applications. The prepared nanofibrous scaffolds were characterized via different experimental techniques and the biocompatibility of the nanofibrous scaffolds was assessed using MTT assay and live/dead cell assay. The wound healing potential of the nanofibrous scaffolds was evaluated through in vivo animal model. Notably, the collagen-coated scaffolds showed improved biocompatibility and fibroblast viability over the uncoated scaffolds. The collagen-coated silk nanofibers containing KH showed good antioxidant properties and promoted wound healing in in vivo studies by minimizing inflammation and enhancing collagen deposition. Thus, the incorporation of antioxidant molecules along with collagen coating enhanced the wound healing efficiency of silk nanofibers.