Insulin resistance is a fundamental defect underlying type 2 diabetes (T2D), which is often associated with excess lipid accumulation in the liver (namely fatty liver). The hepatoprotective drug sophocarpidine (MW: 249) is clinically used for the treatment of viral infections and tumours in the liver. As these conditions are associated with increased lipid synthesis and insulin resistance, we investigated whether sophocarpidine has potential therapeutic effects on insulin resistance and the mechanisms involved. Sophocarpidine (100mg/kg/day) was administrated orally for 4 weeks in C57BL6/J mice after 10-wk high-fat (HF) feeding. Sophocarpidine significantly (p<0.01 for all) reduced body weight (by 15%), adiposity (30%) and hepatic triglyceride level (28%) without affecting caloric intake. HOMA-IR index was significantly reduced (80%, p<0.01) with a 15% and 75% reduction in fasting blood glucose and plasma insulin levels respectively. As expected, sophocarpidine improved glucose tolerance of HF mice by 15% (p<0.01) with up to 70% reduction (p<0.01) of plasma insulin throughout the glucose tolerance test. Consistent with reduced hepatic triglyceride level, sophocarpidine suppressed lipid synthesis as indicated by reduced matured form of SREBP-1c (50%, p<0.01) and SCD-1 (70%, p<0.01). In addition, sophocarpidine acutely increased oxygen consumption (10%, p<0.01) and decreased respiratory exchange ratio (4%, p<0.05) in chow-fed mice after an oral gavage. While there was no detectable activation of AMPK and/or PPARα in the liver of sophocarpidine-treated mice, further study showed that the protein level of HSP70 increased by 50% in the liver of HF mice after sophocarpidine treatment. And the protein level of HSP70 significantly correlated with liver triglyceride level, HOMA-IR and glucose incremental area under the curve (p<0.05). Our data demonstrated that sophocarpidine may be used for the treatment of T2D and associated metabolic disorders, and the molecular action of this hepatoprotective drug involves an activation of HSP70 in the liver.