Abstract: OBJECTIVE To study the influence of Gegen Qinlian Decoction (GGQLD) on SIRT1/FoxO1 signaling pathway in high-fat-induced insulin resistance mice and its mechanism in improving hepatic insulin resistance. METHODS Except those in the normal group， male C57BL/6J mice with insulin resistance were established by feeding high fat diet. Then mice were randomly divided into five groups: high fat diet group， and the four groups treated with low dose of GGQLD， high dose of GGQLD， positive medicine (Pioglitazone)， GGQLD combined with Pioglitazone， respectively. The control group was given equal volume of sterilized water， and the others were given corresponding drugs for 8 weeks. Animals were examined for weight gain， blood glucose and triglyceride. HOMA-IR was calculated. The lipid deposition in liver tissue was detected by HE staining. The protein expression of SIRT1/FoxO1 signaling pathway were detected by Western blot. SIRT1 and FoxO1 mRNA expression were detected by qPCR. RESULTS Compared with the high fat diet group， the body weight， triglyceride， insulin level and HOMA-IR of each group were significantly lower (P<0.01). Liver pathology showed that the liver vacuolation of various doses of Gegen Qinlian Decoction groups and pioglitazone group decreased significantly. The mRNA expression of SIRT1 in these treatment groups were higher than those in the high fat diet group (P<0.05). Compared with the control group， the protein expression of SIRT1 and PPARγ in the high fat diet group was significantly decreased (P<0.05， P<0.01) and the protein expression of acely-FoxO1 and FABP4 increased (P<0.01). After treatment， the protein expression of SIRT1 and PPARγ increased significantly (P<0.05， P<0.01)， and the protein expression of acely-FoxO1 and FABP4 decreased (P<0.05， P<0.01). CONCLUSION Gegen Qinlian Decoction can inhibit acely-FoxO1 and improve hepatic insulin resistance by activating SIRT1/FoxO1 signaling pathway.