Objective To investigate the effect of autologous skin graft combined with acellular dermal matrix on wound repair in patients. Methods Eighty patients undergoing wound repair in the Huaihe Hospital of Henan University from January 2020 to January 2025 were enrolled and randomly divided into conventional group (treated with acellular dermal matrix repair) and study group (treated with autologous skin graft combined with acellular dermal matrix), 40 cases in each group. The differences in skin graft survival rate, wound healing status, wound healing-related factors (vascular endothelial growth factor (VEGF), tissue inhibitor of metalloproteinases-1 (TIMP-1), matrix metalloproteinase-2 (MMP-2)), and inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor- α (TNF- α), soluble inter-cellular adhesion molecule-1 (sICAM-1)) were compared between the two groups. Results The skin graft survival rate, the wound healing rates at 7 and 13 days postoperatively in the study group was significantly higher than those in the conventional group (all P＜0.05), and the wound healing time was significantly shorter than that in the conventional group (P＜0.05). At 7 days postoperatively, the levels of VEGF and TIMP-1 in the study group were significantly higher than those in the conventional group (all P＜0.05), while the levels of MMP-2, IL-6, TNF-α, and sICAM-1 were significantly lower than those in the conventional group (all P＜0.05). Conclusion Autologous skin graft combined with acellular dermal matrix can effectively promote wound healing and improve wound repair outcomes. The mechanism may be related to the regulation of wound healing-related factors and the alleviation of the inflammatory response.