Objective To investigate the protective effects of andrographolide on septic mice and to explore the underlying mechanism. Methods Sepsis model was induced by cecal ligation and puncture (CLP) in mice. A total of 64 C57BL/6 mice were evenly randomized into 4 groups: a sham group, a CLP group, a dimethyl sulfoxide (DMSO) group and an andrographolide (AND) group. The mice were injected intraperitoneally with 0.2 mL normal saline, 0.2 mL 5% DMSO or 0.2 mL andrographolide (10 mg/kg) at 1 h, 6 h and 12 h after surgery. The survival rates were assessed 7 days after surgery and the survival curve was plotted. Another 48 C57BL/6 mice were grouped as above. The peripheral blood, peritoneal lavage fluid (PLF), lung and liver tissues were harvested 24 h after operation. Polymorphonuclear leukocyte (PMN) count in PLF was determined. Bacterial loads in the peripheral blood sample and PLF were also determined. The levels of TNF-α, IL-6 and IL-10 in the blood samples were detected by ELISA. The lung and liver tissues were observed and analyzed by hematoxylin-eosin staining. Results Compared with CLP group, AND group had a significantly increased survival rate 7 days after operation (P<0.01), a significantly decreased PMN count in PLF (P<0.01), a significantly enhanced bacterial clearance capability in both blood and PLF (P<0.01), significantly decreased serum TNF-α and IL-6 levels, significantly increased IL-10 level, and significantly alleviated lung and liver tissue injuries (P<0.01). The above parameters were not significantly different between the DMSO group and CLP group. Conclusion Andrographolide has protective effect against CLP-induced sepsis in mice, which might be associated with regulation of the immunological function, enhancement of bacterial clearance and inhibition of excessive inflammatory response during sepsis.