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Abstract Background Cutaneous wound healing and regeneration have become a recognized health challenge in the world, which causes severe damage to the mental and physical health of patients. Human adipose-derived mesenchymal stem cells (hADSC) play an essential role in wound healing via their paracrine function. Exosomes secreted by hADSC may contribute to this progress. In this study, we investigated the potential clinical application roles of hADSC and hADSC-derived exosomes (hADSC-Exo) in cutaneous wound healing. Methods hADSC-Exo was isolated from human hADSC by ultracentrifugation. Mice were subjected to a full-thickness skin biopsy experiment and treated with either control vehicle or hADSC or hADSC-Exo by smearing administration (sm) or subcutaneous administration (sc) or intravenous administration (iv). The efficacy of hADSC and hADSC-Exo on wound healing was evaluated by measuring wound closure rates, histological analysis. Results Combined application of local hADSC-Exo smearing and hADSC/hADSC-Exo intravenous administration offered the additional benefit of promoting wound healing, accelerating re-epithelialization, reducing scar widths, and enhancing angiogenesis and collagen synthesis. Either topical application of hADSC-Exo or systemic administration with hADSC/hADSC-Exo appeared more effective in stimulating cell proliferation, inhibiting cell apoptosis and inflammation, and promoting skin elasticity and barrier integrity, with increased genes expression of PCNA, VEGF, collagen III, Filaggrin, Loricrin, and AQP3, with decreased genes expression of TNF-alpha. Conclusion Our findings suggest that the combined administration of hADSC/hADSC-Exo can facilitate cutaneous wound healing and reduce scar formation. These data provide the first evidence for the feasibility of smearing of hADSC-Exo as a cell-free therapy in treating cutaneous wounds, and the potential clinical value of combined administration of hADSC/hADSC-Exo.