P53 is a tumor suppressor protein that regulates cell cycle arrest, senescence, and apoptosis. Recent studies suggest that p53 also regulates metabolic processes, including ferroptosis, a non-apoptotic form of cell death. This study shows that p53 inhibits cystine uptake by repressing SLC7A11, a key component of the cystine/glutamate antiporter, thereby sensitizing cells to ferroptosis. The p53 mutant KR, which lacks the ability to induce cell cycle arrest, senescence, or apoptosis, still regulates SLC7A11 expression and induces ferroptosis upon reactive oxygen species (ROS) stress. Analysis of mutant mice shows that these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2. SLC7A11 is highly expressed in human tumors, and its overexpression inhibits ROS-induced ferroptosis and abrogates p53 KR-mediated tumor growth suppression in xenograft models. These findings reveal a new mode of tumor suppression based on p53 regulation of cystine metabolism, ROS responses, and ferroptosis. The study also shows that p53-mediated ferroptosis is involved in embryonic development and the lethality associated with loss of Mdm2. Additionally, p53-mediated ferroptosis is specifically induced by ROS and that SLC7A11 levels are critical for p53-mediated ferroptotic responses. The study highlights the role of p53 in tumor suppression through metabolic regulation and ferroptosis.P53 is a tumor suppressor protein that regulates cell cycle arrest, senescence, and apoptosis. Recent studies suggest that p53 also regulates metabolic processes, including ferroptosis, a non-apoptotic form of cell death. This study shows that p53 inhibits cystine uptake by repressing SLC7A11, a key component of the cystine/glutamate antiporter, thereby sensitizing cells to ferroptosis. The p53 mutant KR, which lacks the ability to induce cell cycle arrest, senescence, or apoptosis, still regulates SLC7A11 expression and induces ferroptosis upon reactive oxygen species (ROS) stress. Analysis of mutant mice shows that these non-canonical p53 activities contribute to embryonic development and the lethality associated with loss of Mdm2. SLC7A11 is highly expressed in human tumors, and its overexpression inhibits ROS-induced ferroptosis and abrogates p53 KR-mediated tumor growth suppression in xenograft models. These findings reveal a new mode of tumor suppression based on p53 regulation of cystine metabolism, ROS responses, and ferroptosis. The study also shows that p53-mediated ferroptosis is involved in embryonic development and the lethality associated with loss of Mdm2. Additionally, p53-mediated ferroptosis is specifically induced by ROS and that SLC7A11 levels are critical for p53-mediated ferroptotic responses. The study highlights the role of p53 in tumor suppression through metabolic regulation and ferroptosis.