Objective To clarify the protective action of a Chinese medicine, Jie-Du-Qu-Yu-Zi-Shen prescription, on the lupus nephritis in MRL/lpr mice through the TLR9-MyD88-NF-κB signaling pathway. Methods Thirty MRL/lpr mice were randomly divided into model group, prednisone group, and traditional Chinese medicine (TCM) group (n=10). Each treatment group received appropriate treatment or drug therapy for 8 weeks. The pathological changes of mouse renal tissues in the three groups were examined and compared using HE, PAS, and Masson staining. Real-time PCR was performed to compare the expression of TLR-9, MyD88, NF-κBm RNA mRNA in each group of the mice. Results Compared with the model group, the Chinese medicine Jie-Du-Qu-Yu-Zi-Shen prescription significantly improved the renal pathological tissue damages in the MRL/lpr mice. Real-time PCR assay showed that the expression levels of TLR-9, MyD88, NF-κB mRNA in the TCM group were significantly lowered (P<0.01 for all). The differences between the TCM group and prednisone group were statistically not significant (P>0.05). Conclusions Jie-Du-Qu-Yu-Zi-Shen prescription has protective effect on the kidney of MRL/lpr mice, alleviating its pathological changes, and delaying the disease course, probably, through inhibiting the TLR-9-MyD88-NF-κB signaling pathway in the kidneys of MRL/lpr mice.