Only humans and higher primates have high uric acid blood levels. Although high uric acid causes gout, it has been linked with human longevity because of its hypothetical antioxidant function. Recent studies reveal that p53 has significant roles in cellular metabolism. One example of this is an antioxidant function that potentially contributes to tumor suppression. Here, we reported a first beneficial link between p53 and uric acid. We identified the uric acid transporter SLC2A9 (also known as GLUT9) as a direct p53 target gene and a key downstream effector in the reduction of reactive oxygen species (ROS) through transporting uric acid as a source of antioxidant. Oxidative stress induced SLC2A9 expression in a p53-dependent manner, and inhibition of SLC2A9 by small interfering RNA (siRNA) or anti-gout drugs such as probenecid significantly increased ROS levels in an uric acid-dependent manner and greatly sensitized cancer cells to chemotherapeutic drugs. Conversely, expression of SLC2A9 reduced ROS and protected against DNA damage and cell death, suggesting its antioxidant function. The increased production of ROS because of p53 loss was rescued by SLC2A9 expression. Furthermore, decreased SLC2A9 expression was observed in several cancer types and was associated with a poorer prognosis. Our findings suggest that the p53-SLC2A9 pathway is a novel antioxidant mechanism that uses uric acid to maintain ROS homeostasis and prevent accumulation of ROS-associated damage that potentially contributes to cancer development.