Vanadium compounds are promising therapeutic agents for the treatment of diabetes and cancer. However, vanadium toxicity has been a great concern. Many works suggested that vanadium-induced oxidative stress is a major reason of vanadium toxicity. Quercetin and green tea polyphenols (GTP) are well-known antioxidants that play important roles in the prevention of many oxidative stress-related diseases. In this study, we investigated the protective effects of quercetin and GTP against damages caused by VO (acac) 2 on isolated mitochondria and whole cells. The experimental results demonstrated that quercetin and GTP could significantly inhibit mitochondrial dysfunctions induced by VO (acac) 2, such as mitochondrial swelling, depolarization of the inner mitochondrial membrane potential (Δψ m), and increased release of reactive oxygen species (ROS). Moreover, they also reduce cytotoxicity in Hep G2 cells. These results indicated that use of natural antioxidants to control the metal toxicity of vanadium compounds may be a promising strategy for developing metal-based therapeutic agents.