Autophagy is a homeostatic process by which damaged organelles such as mitochondria are degraded by an autophagosomal regulated pathway. Accordingly, excessive autophagy can be detrimental and promote cell death. Herein, we provide new compelling evidence that mitophagy and necrotic cell death induced by the chemotherapy drug doxorubicin are obligatorily linked to and mutually dependent upon the Bcl-2 protein Bnip3. In contrast to saline treated mice, a marked increase in mitochondrial targeting of Bnip3 was observed in hearts of mice treated with DOX. This coincided with severe morphological defects, including recruitment of Parkin to mitochondria, increased co-localization of Bnip3 and LC3II and numerous cytoplasmic vesicles containing mitochondria - indicative of increased mitophagy. Interestingly, mitophagy was accompanied by an increase necrosis markers Lactate Dehydrogenase (LDH), Troponin T (cTnT) and loss of nuclear High Mobility Group Box 1 (HMGB1). Further, while mitochondria of wild type mouse embryonic fibroblasts (MEFs) treated with DOX, were severely damaged, resulting in mitophagy and necrotic cell death, Bnip3 - /- MEFs were resistant to the cytotoxic effects of doxorubicin. Conversely, inhibition of autophagy with 3-Methyl Adenine (3-MA), knock-down of Atg 7 or Bnip3 suppressed mitophagy and necrotic cell death of cardiac myocytes treated with DOX. Concordantly, mice deficient for Bnip3 were resistant to mitochondrial injury and mitophagy induced by DOX and exhibited lower mortality than corresponding wild type mice treated with doxorubicin. To our knowledge our data provide the first direct evidence that mitophagy induced by DOX is maladaptive and leads to necrotic cell death by a mechanism that is mutually dependent upon and obligatorily linked to Bnip3. Interventions that mitigate abnormal mitophagy may provide beneficial in suppressing necrotic cell death and cardiac dysfunction in cancer patients treated with doxorubicin.