The present study was designed to investigate the anti-sepsis effects of physcion 8- O- β-glucopyranoside (POG) isolated from Rumex japonicas and explore its possible pharmacological mechanisms. POG was extracted from R. japonicas by bioactivity-guided isolation with the anti-sepsis agents. Survival analysis in septic mouse induced by LPS and heat-killed Escherichia coli were used to evaluate the protective effect of POG (40 mg·kg −1, i.p.) on sepsis. Cytokines including TNF-α, IL-1β and IL-6 in RAW 264.7 cells induced by LPS (100 ng·mL −1) were determined by ELISA. In addition, the proteins expressions of TLR2 and TLR4 were determined by Western blotting assay. Our results demonstrated that POG (40 mg·kg −1, i.p.) possessed significant protective activity on the endotoxemic mice. The POG treatment (20, 40, and 80 μg·mL −1) significantly decreased the TNF-α, IL-1β and IL-6 induced by LPS ( P < 0.01) in a concentration-dependent manner. Furthermore, the TLR4 and TLR2 proteins were also down-regulated by POG at 20 ( P < 0.01), 40 ( P < 0.01), and 80 μg·mL –1 ( P < 0.01). The present study demonstrated that the POG extracted from R. japonicas possessed significant anti-sepsis effect on endotoxemic mice, and can be developed as a novel drug for treating sepsis in the future.