Traditionally, the p21 protein has been viewed as limiting cancer progression and promoting aging. In contrast, there are reports that p21 can enhance cancer survival and limit tissue damage, depending on the tissue of origin and type of stressor involved. Here, we provide evidence to support these latter two roles of p21 by exploring its ability to regulate ferroptosis. Ferroptosis is a form of cell death that is associated with certain degenerative diseases, some of which are aging-related. Our results reveal a correlation between p21 protein levels in cell lines that are resistant to ferroptosis (p21 high) versus cell lines that are sensitive and easily undergo ferroptosis (p21 low). We also show that p21 levels themselves are differentially regulated in response to ferroptosis in a p53-independent manner. Further, experimentally altering the abundance of p21 protein inverts the ferroptosis-sensitivity of both resistant and sensitive human cancer cell lines. Our data also indicate that the interaction of p21 with CDKs is crucial for its ability to restrict the progression of ferroptosis. While this study was performed in cancer cell lines, our results support the potential of p21 to aid in maintenance of healthy tissues by blocking the damage incurred due to ferroptosis.