Systemic lupus erythematosus (SLE) is a serious disorder of immune regulation characterized by over-production of autoantibodies, lupus nephritis, CD4+ T cell abnormal activation, and immune complex-mediated inflammation. Chronic graft versus host disease (cGVHD) mouse model is a well-established model of SLE. Quercitrin is a natural compound found in Tartary buckwheat with a potential anti-inflammation effect that is used to treat heart and vascular conditions. In our previous study, we determined that quercitrin is an immunosuppressant with beneficial effects in mouse models of immune diseases. We hypothesized that quercitrin could prevent lupus nephritis in the cGVHD mouse model by decreasing the production of autoantibodies and inflammatory cytokines, and reducing immune cell activation. cGVHD was induced by injecting DBA/2 spleen cells into the tail vein of BDF1 mice. The cGVHD mice exhibited a significant proteinuria, which is a marker of nephritis. Quercitrin decreased the amount of serum antibodies, CD4+ T cell activation, as well as the expression levels of T-bet, GATA-3, and selected cytokines. Moreover, quercitrin treatment decreased the expression of inflammatory genes and cytokines in the kidney, as well as in peritoneal macrophages. In addition, quercitrin inhibited LPS-induced cytokines as well as the phosphorylation of extracellular-signal regulated kinase, p38 MAPK and c-Jun N-terminal kinase in Raw264.7 cells. Overall, quercitrin ameliorated the symptoms of lupus nephritis in the cGVHD mouse model, which may be due to the inhibition of CD4 T cell activation and anti-inflammatory effects on macrophages.