MiR-33a and miR-122 are major regulators of lipid metabolism in the liver and their deregulation has been linked to the development of metabolic diseases such as obesity and metabolic syndrome. The aim of this study was to evaluate whether the level of miR-33a and miR-122 in rat liver correlate with obesity and potential anti-obesity effect of grape seed extract (GSE) and calorie restricted diet with special emphasis on dyslipidemia, oxidative stress and inflammation. Rats received high fat diet (HFD) for four months to induce obesity. Animals which had ≥30% increase in body weight were selected in this study. Obese rats were divided into 4 groups (n=12/each) and treated for 8 weeks with caloric restriction, GSE (30 mg/kg daily orally) alone or in combined form. Obese rats developed increased body weight and up-regulation of miR-33a and mir-122 in the liver. Also obesity provoked dyslipidemia, oxidative stress and inflammatory status. Importantly, GSE alleviated all deleterious effects of HFD especially when administered with calorie restricted diet. They counteracted the increase of these two miRNAs with improvement in dyslipidemia, oxidative and inflammatory processes. The results reported suggested that beneficial metabolic effects of GSE in combination with dietary treatment could be useful to treat obesity and metabolic disorders. Key words: Obesity, GSE, dyslipidemia, oxidative stress, hepatic miRNAs