High-mobility group box 1 (HMGB1) mobilizes platelet-derived growth factor receptor alpha-positive (PDGFRα(+)) mesenchymal cells from bone marrow (BM) into circulation. However, whether HMGB1-induced endogenous PDGFRα(+) mesenchymal cells stimulate skin regeneration has been unclear. Here, we investigated the functions of the HMGB1/BM-PDGFRα(+) mesenchymal cell axis in the regeneration of mouse skin grafts. We found that intravenous HMGB1 administration induced an accumulation of endogenous BM-PDGFRα(+) mesenchymal cells followed by significant inflammatory suppression in the grafts. In contrast, mice with reduced BM-PDGFRα(+) mesenchymal cells showed massive inflammation of the grafts compared to mice that had normal levels of these cells even after HMGB1 administration, suggesting that BM-PDGFRα(+) mesenchymal cells contribute to the HMGB1-induced anti-inflammatory effect. We also found that intravenously administered HMGB1 augmented the local migration of BM-PDGFRα(+) mesenchymal cells from circulation to skin graft by inducing the expression of CXCR4, an SDF-1 receptor, on these cells. Finally, we showed the therapeutic activity of the HMGB1/BM-PDGFRα(+) mesenchymal cell axis in an allergic contact dermatitis model. The results illustrated the contribution of the HMGB1/BM-PDGFRα(+) mesenchymal cell axis in suppressing the inflammation of injured/inflamed skin. These findings may provide future perspectives on the use of HMGB1-based medicines for intractable diseases.