Cardiovascular diseases rank as the primary cause of mortality worldwide, with myocardial infarction (MI) being a predominant contributor. MI results in extensive cardiomyocyte death and cardiac fibrosis development. Notably, the myocardium comprises diverse cell types, with cardiac myocytes and fibroblasts being the most abundant. One of the underlying mechanisms of MI is autophagy disruption. Autophagy is a highly conserved cellular process that selectively eliminates damaged organelles, oxidizes lipids, and protein aggregates to maintain cellular integrity. Impaired autophagy compromises cellular processes, leading to adverse effects. Previous research from our lab discovered that impaired autophagy increased cardiomyocyte death and exacerbated cardiac damage following ischemia. In this study, given the cellular diversity of the myocardium, we investigated whether cardiac fibroblasts at passage 0 (P0-activated myofibroblasts) and passage 1 (P1-myofibroblasts) also exhibit altered sensitivity to hypoxia induced autophagy, a condition associated with MI. Notably, in contrast to normoxic controls, hypoxia triggered widespread death in cardiomyocytes compared to P0 and P1. Additionally, hypoxia caused pronounced mitochondrial network fragmentation in cardiac myocytes, indicative of fission with milder effects in P1. Mitochondrial fission in cardiomyocytes was induced by upregulated DRP, phospho-DRP1 (Ser616), and downregulated phospho-DRP1 (Ser637). These regulators remained unchanged in fibroblasts, highlighting a distinctive regulatory pattern of fission in cardiac myocytes versus fibroblasts. Fundamentally, hypoxia induced the opening of mitochondrial permeability transition pore (mPTP), reduced autophagic flux and markedly impaired mitophagy in cardiomyocytes, resulting in dysfunctional mitochondria accumulation. Conversely, hypoxia had no discernible effects on mPTP, autophagy or mitophagy in P0 or P1. Moreover, we identified BNIP3 (BCL-2 interacting protein-3) as a key regulator of apoptosis and mitophagy inducer in cardiomyocytes, to be upregulated in all cell types, while the activated homodimeric BNIP3 form was specifically increased in cardiomyocytes. The heightened expression of the monomeric BNIP3 in fibroblasts suggests a protective mechanism that prevents BNIP3 dimerization and cell death in cardiac fibroblasts versus myocytes, thereby providing a tentative mechanism for which fibroblasts avert apoptosis. In conclusion, this study reveals the differential impact of hypoxia on adaptive signaling pathways such as autophagy that influence mitochondrial injury and cell death within cardiac myocytes and fibroblasts.