Scope This study investigated the effects of resveratrol (RV) on diabetes‐related metabolic changes in a spontaneous model of type 2 diabetes, as well as activation of AMP‐activated protein kinase (AMPK) and downstream targets. Methods and results C57BL/KsJ‐db/db mice were fed a normal diet with RV (0.005% and 0.02%, w/w) or rosiglitazone (RG, 0.001%, w/w) for 6 weeks. Both doses of RV significantly decreased blood glucose, plasma free fatty acid, triglyceride, apo B/apo AІ levels and increased plasma adiponectin levels. RV activated AMPK and downstream targets leading to decreased blood HbA1c levels, hepatic gluconeogenic enzyme activity, and hepatic glycogen, while plasma insulin levels, pancreatic insulin protein, and skeletal muscle GLUT4 protein were higher after RV supplementation. The high RV dose also significantly increased hepatic glycolytic gene expression and enzyme activity, along with skeletal muscle glycogen synthase protein expression, similar to RG. Furthermore, RV dose dependently decreased hepatic triglyceride content and phosphorylated I kappa B kinase (p‐IKK) protein expression, while hepatic uncoupling protein (UCP) and skeletal muscle UCP expression were increased. Conclusion RV potentiates improving glycemic control, glucose uptake, and dyslipidemia, as well as protecting against pancreatic β‐cell failure in a spontaneous type 2 diabetes model. Dietary RV has potential as an antidiabetic agent via activation of AMPK and its downstream targets.