One of the main features of cancer is the high rate of cell proliferation and growth. To do this, cancer cells need to redirect their metabolism mainly towards anaerobic glycolysis and an increased mitochondrial glutamine energy metabolism. Sirtuins are cellular proteins with regulatory functions on metabolic pathways, genomic stability, apoptosis, longevity, inflammation, energy metabolism and oxidative stress. Sirtuins have emerged recently as a potential therapeutic option to treat several chronic diseases including cancer. This review summarizes the tumor suppressor function of Sirtuin 3 (SIRT3), highlighting its repressor effect on glycolytic metabolism, promoting mitochondrial metabolism and oxidative stress reduction. SIRT3 activation by exercise is particularly described since it may represent a potent tool for several types of cancer treatment.