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<i>Introduction</i>: Despite decades of research, obesity and its related medical complications remain a major health concern globally. Therefore, novel therapeutic strategies are needed to combat obesity and its numerous debilitating complications. Resveratrol (RES) has a potential therapeutic effect in obesity and diabetes by improving oxidative metabolism and insulin signaling. <i>Background and Objectives</i>: The aim of this study was to investigate the effect of RES treatment on weight loss and glucose and fatty acid metabolism. Methods: Obesity was induced in 24 mice by exposure to a high-fat diet (HFD) for 8 weeks. Mice were randomly assigned to one group of either: group 1: control, non-treated low-fat diet (LFD) for 12 weeks (<i>n</i> = 8), group 2: non-treated high-fat diet (HFD) for 12 weeks (<i>n</i> = 8), group 3: RES-treated HFD (HFD + RES) (<i>n</i> = 8), or group 4: RES-treated and switched to LFD (HFD-LFD + RES) (<i>n</i> = 8). HFD + RES mice were first fed an HFD for 8 weeks followed by 4 weeks of RES. The HFD-LFD + RES group was first fed an HFD for 8 weeks and then treated with RES and switched to an LFD for 4 weeks. <i>Results</i>: After 12 weeks, group 2 mice had significantly higher body weights compared to group 1 (23.71 ± 1.95 vs. 47.83 ± 2.27; <i>p</i> < 0.05). Group 4 had a significant decrease in body weight and improvement in glucose tolerance compared to mice in group 2 (71.3 ± 1.17 vs. 46.1 ± 1.82 and 40.9 ± 1.75, respectively; <i>p</i> < 0.05). Skeletal muscles expression of SIRT1, SIRT3, and PGC1α were induced in group 3 and 4 mice compared to group 2 (<i>p</i> < 0.01), with no changes in AMP-activated protein kinase expression levels. Furthermore, combination of RES and diet ameliorated skeletal muscle intermediate lipid accumulation and significantly improved insulin sensitivity and secretion. <i>Conclusions</i>: The results of this study suggest a synergistic beneficial effect of LFD and RES to lower body weight and enhance glucose and fatty acid metabolism.