Graft-versus-host disease (GVHD) as a major complication after allogeneic hematopoietic stem cell transplantation is not well prevented now. We have observed that interleukin-22 (IL-22) produced by Th22, Th1, and Th17 cells participated in GVHD development in our previous study. However, the role of IL-22 in GVHD is still ambiguous. The aim of this study was to illuminate the pathological or protective function and the potential mechanism of IL-22 in the GVHD process. In the present study, we found that compared with mice cotransferred with bone marrow and spleen cells (BS mice) without IL-22 administration, more serious tissue damage and higher GVHD clinical score were observed in BS+IL-22 mice. IL-22 administration was a benefit to early recovery of thymus after irradiation-induced injury. Administration of IL-22 could promote Th1 and Tc1 cell expansion in mesenteric lymph nodes but reduce CD4⁺CD25⁺Foxp3⁺ regulatory T (Treg) cell number. Levels of systemic inflammatory cytokines (IFN-γ and TNF-α) were upregulated, while the level of immunosuppressive cytokine IL-10 was downregulated in recipients with IL-22 injection. In conclusion, IL-22, which exacerbates both local immune responses and systemic inflammation of recipients, plays a pathogenic role in the GVHD process. The potential mechanism of IL-22 in GVHD may attribute to increased alloreactive effector Th1 and Tc1 cells and decreased inhibitory Treg cell.