(5R)-5-Hydroxytriptolide (LLDT-8), a triptolide derivative with low toxicity, was previously reported to have strong immunosuppressive effects both in vitro and in vivo, but it remains unknown whether LLDT-8 has a therapy effect on systemic lupus erythematosus. In this study, we aimed to investigate the therapeutic effects of LLDT-8 on lupus nephritis in MRL/lpr mice, a model of systemic lupus erythematosus. Compared with vehicle group, different clinical parameters were improved upon LLDT-8 treatment: prolonged life-span of mice, decreased proteinuria, downregulated blood urea nitrogen and serum creatinine, reduced glomerular IgG deposits, and ameliorated histopathology. A decreased expression of the inflammatory cytokines IFN-, IL-17, IL-6, TNF-α was also observed in the kidney of LLDT-8 treated MRL/lpr mice. Moreover, infiltration of T cells into kidney was mitigated after LLDT-8 treatment, which was corresponding with decreased expression of related chemokines IP-10, Mig, and RANTES in kidney. The proportion of macrophage and neutrophil cells and related chemokines expression were also reduced in kidney of LLDT-8 treated mice. In human proximal tubule epithelial cell line and mouse mesangial cell line, consistent with our in vivo experiment results, LLDT-8 suppressed the expression of related chemokines and IL-6. In summary, LLDT-8 has a therapeutic benefit for lupus nephritis via suppressing chemokines expression and inhibiting immune cells infiltration in kidneys of MRL/lpr mice.