Liver steatosis is characterized by an abnormal accumulation of triacylglycerols in this organ. This metabolic disorder is closely associated with obesity. In the present study, we aimed to analyse the effect of a combination of resveratrol and quercetin on liver steatosis in an animal model of dietetic obesity, and to compare it with one induced by the administration of each polyphenol separately. Rats were divided into four dietary groups of nine animals each and fed a high-fat, high-sucrose diet: an untreated control group and three groups treated either with resveratrol (RSV; 15 mg/kg/day), with quercetin (Q; 30 mg/kg/day), or with both (RSV + Q; 15 mg resveratrol/kg/day and 30 mg quercetin/kg/day) for 6 weeks. Liver weight and triacylglycerol content decreased only in the RSV + Q group. A significant reduction in acetyl-CoA carboxylase activity was observed in RSV and RSV + Q groups, without changes in fatty acid synthase activity. A significant increase in carnitine palmitoyltransferase-1a activity was observed only in rats treated with the combination of resveratrol and quercetin, suggesting increased fatty acid oxidation. Citrate synthase, a marker of mitochondrial density, remained unchanged in all groups. No significant changes were observed in the expression of peroxisome proliferator-activated receptor α (PPARα), nuclear respiratory factor 1 (NRF-1) and transcription factor A mitochondrial (TFAM). In conclusion, resveratrol and quercetin together, combining two doses which were shown to be ineffective singly, is an interesting tool to prevent liver steatosis associated with high-fat high-sucrose feeding. The delipidating effect seems to be mediated by increased fatty acid oxidation not associated with increased mitochondriogenesis, and by reduced de novo lipogenesis.