Mesenchymal stem cells (MSCs) have become a promising therapeutic strategy for scleroderma. Exosomes derived from MSCs (MSC-exosomes) possess functional properties similar to those of their source cells. In this study, we aimed to explore their potential role of MSC-exosomes in the treatment of scleroderma. MSC-exosomes were isolated from human umbilical cords via ultra-centrifugation and characterized. An experimental fibrosis model was established in BALB/c mice by a subcutaneous injection of bleomycin (BLM), followed by treatment with MSC-exosomes or MSC infusions once a week for a total of four doses. Using hematoxylin and eosin and Masson's trichrome staining and immunohistochemistry, hydroxyproline content, and quantitative real-time PCR analyses, we investigated the effects of MSC-exosomes on dermal fibrosis and explored the underlying mechanism. MSC-exosome treatment restored the dermal architecture, reduced dermal thickness, and partially increased subcutaneous adipose tissue thickness. In addition, MSC-exosomes inhibited the expression of collagen (COL)-I, COL-III, and α-smooth muscle actin. The transforming growth factor (TGF)-β/Smad signaling pathway was also suppressed in MSC-exosome-treated mice. Taken together, our results suggest that MSC-exosomes can attenuate myofibroblast activation and collagen deposition in dermal fibrosis by downregulating the TGF-β/Smad signaling pathway. Therefore, the use of MSC-exosomes may be a potential therapeutic approach for the treatment of scleroderma.