Treatment of systemic lupus erythematosus (SLE), a chronic inflammatory disease, involves the long-term use of immunosuppressive agents with significant side effects. New therapeutic approaches are being explored to find better treatment possibilities. In this study, age-matched female MRL/lpr mice were treated orally with a natural flavonoid astilbin. Astilbin administration started either at week 8 or week 12 of age though week 20. In the early treatment regimen, the treatment with astilbin reduced splenomegaly/lymphomegaly, autoantibody production and ameliorated lupus nephritis. Several serum cytokines were significantly decreased upon treatment including IFN-g, IL-17A, IL-1b, TNF-a and IL-6. Both spleen CD44 hi CD62L lo activated T cells and CD138+B220- plasma cells greatly declined. Furthermore, astilbin treatment resulted in decreased mitochondrial membrane potential in activated T cells and downregulated expression of the co-stimulatory molecules CD80 and CD86 on LPS stimulated B cells. Similar but less profound effectiveness was observed in the mice with established disease in the late treatment regimen. These results indicate that the natural product astilbin can mitigate disease development in lupus-prone mice by decreasing functional activated T and B cells.