The aim of this study was to investigate the effects of the combination of sodium ferulate (SF) and oxymatrine (OMT) on mice with cecal ligation and puncture (CLP)-induced sepsis. Swiss male mice were randomly divided into a control group, CLP group, three SF + OMT groups (3.1+6.9; 6.2+13.8 and 12.3+27.7 mg/kg), SF (6.2 mg/kg) group and OMT (13.8 mg/kg) group. Eight hours after the administration of the drugs, the survival rates and survival times of the animals were monitored. In addition, the lung wet/dry weight (W/D) ratio; alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels in the serum; the C-reactive protein (CRP), interleukin-6 (IL-6) and interferon-γ (IFN-γ) levels in the serum and lung and liver homogenates; and the malondialdehyde (MDA) and superoxidase dismutase (SOD) levels in the lung and liver homogenates were measured. The bacterial load in the serum was also studied. Following treatment with the combination of SF and OMT, the survival rate increased and the survival time was prolonged; CLP-induced increases in the lung W/D ratio and the levels of ALT, AST, LDH, CRP, IL-6, IFN-γ and MDA were significantly reduced; and the SOD activity levels were increased, compared with those of the untreated animals with CLP-induced sepsis. These results indicated that the combination of SF and OMT induced protective effects against CLP-induced lethal sepsis of mice. The possible mechanism of these effects may be associated with the alleviation of systemic inflammation and diminishment of oxidative injury.