Graft-versus-host disease (GVHD) is a multi-system disease after hematopoietic stem cell transplantation and a kind of specific immune phenomenon, which is caused by donor derived immunocompetent cells. Nuclear factor-κappa B NF-κB is a DNA-binding protein with transcriptional regulatory activity, playing an important role in the activation of immunologic cells in acquired and innate immunity or cytokine production. This process leads to immune activation and the development of GVHD. Studies indicate that bortezomib, an inhibitor of NF-κB, can suppress the activation of lymphocytes by blocking the NF-κB signaling pathway and prevent the development and progression of GVHD. Therefore, it is feasible to use bortezomib to prevent and treat GVHD. In this paper, we will give an overview of the NF-κB signaling pathway and the pharmacological action of bortezomib on GVHD and review the recent advances in the prevention and treatment of GVHD using bortezomib.