Significance Our work identifies regulatory mechanisms between ferroptosis and autophagy. We discovered that PE-binding protein-1 (PEBP1) is pivotal for dynamic interactions between the ferroptotic cell death program and prosurvival autophagy in asthmatic/Type 2 stimulated airway epithelial cells and that concurrent activation of autophagy protects cells from ferroptotic death and mitochondrial DNA release. Similar findings are observed in Type 2 Hi asthmatic epithelial cells where high 15-lipoxygenase-1 (15LO1)–PEBP1 and light chain-3 II (LC3-II) levels associate with low bronchoalveolar lavage fluid mitochondrial DNA and severe disease. Our findings of concomitant activation of ferroptosis and autophagy by 15LO1–PEBP1 complexes and their hydroperoxy-phospholipids reveal a pathobiologic pathway relevant to asthma and amenable to therapeutic targeting.