Ellagic acid (EA), a natural polyphenol compound that exists in a variety of fruits and vegetables, has been reported to inhibit tumor growth by reducing cell growth, inducing apoptosis, and damaging mitochondria. Recent reports demonstrate that mitochondria regulate cancer cell death through energy metabolism and that different types of cell death coexist in vivo. We showed that EA inhibited lung cancer cell proliferation, markedly decreased ATP levels, decreased the potential of the inner mitochondrial membrane and decreased oxygen consumption in vitro. In addition, EA activated AMP-activated protein kinase (AMPK) and reduced HIF-1α in lung cancer cells. Moreover, the treatment of tumor-bearing mice with EA dramatically inhibited tumor growth, increased p-AMPK and suppressed HIF-1α levels. These findings suggest that EA could be a promising chemotherapeutic agent that targets mitochondrial metabolism in lung cancer.