Resveratrol reportedly promotes the improvement of cardiac dysfunction and other cardiovascular diseases. Studies demonstrate resveratrol exhibits a set of benefits, including anti-oxidative property, anti-apoptosis and anti-inflammation. However, the molecular mediators of resveratrol-induced cardiac benefits are still not fully disclosed. Present study aims to investigate whether estrogen-related receptor (ERR)-α, an orphan nuclear receptor, determines the protective benefits of resveratrol in obesity-related cardiomyopathy. Through high fat diet-fed mouse model, our results show resveratrol increases cardiac ERR-α level and attenuates diet-induced cardiac hypertrophy, mitochondrial inactivity and inflammatory response. Co-administration of lentivirus encoding Err-α siRNA abolishes these benefits, such as enlargement of cardiomyocyte size, induction of left ventricular dysfunction and structural disorders. More importantly, we firstly find resveratrol stimulates the cardiac mitochondrial activities, but silencing Err-α decreased mitochondrial function on ATP production, oxygen consumption and complex I activity. Besides, Err-α deficiency also reverses resveratrol-mediated suppression of inflammatory response in cardiac tissues. Present study not only shows resveratrol enhances cardiac mitochondrial activities, but also supports ERR-α at least partially controls the pharmacological benefits of resveratrol in obese mouse cardiomyopathy.