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. 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, ip) on sepsis. Cytokines including TNF-α, IL 1β and IL-6 in RAW 264.7 cells were determined by ELISA (100 ng · mL -1) respectively. POG (40 mg · kg -1, ip) possessed significant protective activity on the endotoxemic mice. The POG treatment (20, 40, and 80 μg · mL -1) -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) possessed significant anti-sepsis effect on endotoxemic mice, and can be developed as a novel drug for treating sepsis in the future.