OBJECTIVE： To investigate the effects of total flavonoids from Psidium guajava leaves （GLTF） on the related factors for estrogen-associated receptor γ（ERRγ）/cyclic adenosine monophosphate responsive element binding protein H（CREBH）pathway in liver of type 2 diabetes mellitus（T2DM）model mice， and to investigate the specific mechanism of its hypoglycemic effect. METHODS： Healthy male ICR mice were collected. T2DM models were established by high-sugar and high-fat diet feeding combined with repeated intraperitoneal injection of low dose streptozotocin. According to the blood glucose value， model mice were randomly divided into model group， metformin group（positive control， 0.17 g/kg），Xiaoke jiangtang capsule group（positive control， 0.75 g/kg），GLTF low-dose and high-dose groups（0.047， 0.094 g/kg）， with 12 mice in each group. Another 12 normal mice were included in normal group. Except that normal group and model group were given constant volume of water intragastrically， other groups were given relevant solution 10 mL/kg intragastrically， qd， for consecutive 21 d. After administration， fasting blood glucose and serum insulin levels of mice were measured and insulin sensitivity index （ISI） was calculated. Histopathological changes of liver and pancreas were observed by HE staining. The protein expressions of ERRγ and CREBH in liver tissues were detected by immunoblotting. The mRNA expression of peroxisome proliferator-activated receptor-γ coactivator-1α（PGC1α）and CREB protein co-activator 2（TORC2）in liver tissue of mice were measured by RT-PCR. RESULTS： Compared with normal group， the levels of fasting blood glucose and serum insulin in T2DM mice were significantly increased in model group， while ISI was decreased significantly （P＜0.01）. The pathological changes of liver tissue were obvious and a large number of vacuoles could be seen. The number and volume of islets in pancreatic tissue decreased， and islet cells showed mild vacuolar lesions. The protein expression of ERRγ and CREBH， mRNA expression of PGC1α and TORC2 in liver tissue were increased significantly （P＜0.01）. Compared with model group， above blood glucose， insulin indexes and pathological changes were improved significantly in GLTF groups. Protein expression of ERRγ and CREBH， mRNA expression of PGC1α and TORC2 in liver tissue were decreased significantly （P＜0.05 or P＜0.01）. CONCLUSIONS： GLTF showed obvious hypoglycemic effect on T2DM model mice； its mechanism might be related to inhibiting ERRγ/CREBH signaling pathway.