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Sepsis is a life‐threatening organ dysfunction that endangers patient lives and is caused by an imbalance in the host defense against infection. Sepsis continues to be a significant cause of morbidity and mortality in critically sick patients. Oxymatrine (OMT), a quinolizidine alkaloid derived from the traditional Chinese herb Sophora flavescens Aiton, has been shown to have anti‐inflammatory effects on a number of inflammatory illnesses according to research. In this study, we aimed to evaluate the therapeutic effects of OMT on sepsis and explore the underlying mechanisms. We differentiated THP‐1 cells into THP‐1 macrophages and studied the anti‐inflammatory mechanism of OMT in a lipopolysaccharide (LPS)‐induced THP‐1 macrophage sepsis model. Activation of the receptor for advanced glycation end products (RAGE), as well as NF‐κB, was assessed by Western blot analysis and immunofluorescence staining. ELISA was used to measure the levels of inflammatory factors. We found that OMT significantly inhibited HMGB1‐mediated RAGE/NF‐κB activation and downstream inflammatory cytokine production in response to LPS stimulation. Finally, an in vivo experiment was performed on septic mice to further study the effect of OMT on injured organs. The animal experiments showed that OMT significantly inhibited HMGB1‐mediated RAGE/NF‐κB activation, protected against the inflammatory response and organ injury induced by CLP, and prolonged the survival rate of septic mice. Herein, we provide evidence that OMT exerts a significant therapeutic effect on sepsis by inhibiting the HMGB1/RAGE/NF‐κB signaling pathway. [ABSTRACT FROM AUTHOR]