AIM: To explore the possible mechanism of Xiaokeshu recipe in the treatment of type 2 diabetes mellitus (T2DM) by observing the effects of Xiaokeshu Recipe on serum inflammatory factors. METHODS: Male SPF-grade SD rats were fed with high-fat and high-sugar fodder combined with intraperitoneal injection of streptozotocin (STZ) to prepare the model of T2DM. The model rats were randomly divided into a model group,a metformin group, low and high-dose Xiaokeshu recipe groups, and a normal group was set up. After successful modeling, the metformin group and the Xiaokeshu recipe groups were treated with metformin and Xiaokeshu recipe by gavage respectively, normal saline was given by gavage in the normal group and the model group. The general living status of rats before and after treatment was observed. After 4 weeks of drug intervention, serum samples and ileum tissue of rats were collected for biochemical and Western blot. RESULTS: As compaed with the model group,the polydipsia and polyuria in the low and high-dose Xiaokeshu recipe and the metformin groups could be improved. As compaed with the model group, the levels of fasting blood glucose (FBG), fasting insulin (FINS) and interleukin-1β (IL-1β) of rats in the low-dose Xiaokeshu recipe group were decreased, but the differences were statistically insignificant (P0.05), the levels of FBG, FINS and IL-1β of rats in the high-dose Xiaokeshu recipe and the metformin groups were significantly decreased as compared with the the model group (P 0.05 or P0.01). As compaed with the model group, the levels of Lipopolysaccharide (LPS), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in the high-dose Xiaokeshu recipe and the metformin groups were decreased (P<0.05 or P<0.01). As compared with the model group, the expressions of toll-like receptor 4 (TLR4) and nuclear transcription factor (NF-κB) protein in ileal tissue were down-regulated in the low and high-dose Xiaokeshu Recipe and the metformin groups (P<0.05 or P<0.01). CONCLUSION: Xiaokeshu recipe may reduce the level of serum LPS, inhibit the TLR4/NF-κB signaling pathway, and reduce the release of inflammatory factors, thus improving insulin resistance and reducing the blood sugar of the body.