The epidemic of obesity and diabetes is growing rapidly. One of the hallmarks of metabolic disease is compromised quality of mitochondria, the key energy producer. Research has demonstrated that mitochondrial biogenesis and autophagy (mitophagy) work in concert to regulate the homeostasis of this organelle in the cell. As a nutraceutical found in grapes, berries, peanuts, and associated foods, resveratrol (RSV) can improve mitochondrial health through activating an energy sensor Sirt1. In this chapter, we review the evidence of the RSV–Sirt1 axis in the regulation of mitochondrial and metabolic homeostasis, with a focus on the molecular network that links RSV and Sirt1 to mitochondrial biogenesis, dynamics, and autophagy in different tissues. Results from preclinical studies and clinical trials have demonstrated the potential of RSV in curbing metabolic disorders, while further studies are warranted to establish the dosage, effectiveness, and toxicity.