Objective  To analyze the protective effect of luteolin on the pancreas of mice with severe acute pancreatitis and to explore its possible molecular mechanism.   Methods  Sixty healthy male C57/BL mice of SPF grade were divided into three groups according to the random number table method, the control group, the severe acute pancreatitis (SAP) model group and the treatment group, 20 cases in each group. The model was established by the caerulein method. The levels of lipase, amylase, heme oxygenase（HO）-1, tumor necrosis factor（TNF）-α, malondialdehyde（MDA）and superoxide dismutase（SOD）were measured by ELASA method . The protein and mRNA levels of nuclear factor（NF)-κB, P38 and p-P38 in each group were determined by Western blotting and Real-time PCR.   Results  Compared with the control group, the pancreas dry-wet weight ratio, lipase and amylase, inflammatory factors Ho-1, TNF-α levels, oxidative stress index MDA levels increased significantly, while SOD levels were significantly lower in the model group and the treatment group (P<0.05). Compared with the model group, the pancreas dry-wet weight ratio, lipase and amylase, TNF-α and MDA levels in the treated group decreased significantly, while HO-1 and SOD levels increased significantly (P<0.05). Compared with the control group, the levels of NF-κB and p-P38 protein and mRNA in the model group and the treatment group increased significantly (P<0.05), and there was no significant change in P38 mRNA protein and expression level (P>0.05). Compared with the model mice, the levels of NF-κB, p-P38 protein and mRNA in the treated group decreased significantly (P<0.05).   Conclusion  Luteolin has a protective effect on SAP mice. Its possible molecular mechanism is to relieve inflammatory stress and oxidative stress, and down-regulate the expression of NF-κB and p-P38 protein.