Combat or burn injuries are associated with a series of risks, such as microbial infection, an elevated level of inflammatory response, and pathologic scar tissue formation, which significantly postpone wound healing and also lead to impaired repair. Skin engineering for wound healing requires a biomimetic dressing substrate with ideal hydrophilicity, holding antioxidant and antimicrobial properties. In addition, available bioactive specification is required to reduce scar formation, stimulate angiogenesis, and improve wound repair. In this study, we successfully fabricated chitosan (Ch)–based hydrogel enriched with isolated exosome (EXO) from easy‐accessible stem cells, which could promote fibroblast cell migration and proliferation in vitro. Full‐thickness excisional wound model was used to investigate the in vivo dermal substitution ability of the fabricated hydrogel composed Ch and EXO substrates. Our finding confirmed that the wounds covered with Ch scaffold containing isolated EXO have nearly 83.6% wound closure ability with a high degree of re‐epithelialization, whereas sterile gauze showed 51.5% of reduction in wound size. In summary, obtained results imply that Ch‐glycerol‐EXO hydrogel construct can be utilized at the full‐thickness skin wound substitution and skin tissue engineering.