Circular RNAs (circRNAs) have important roles in several cellular processes. No study has established the pathophysiological role for circRNAs in the heart. Here, we show that a circRNA (mitochondrial fission and apoptosis-related circRNA (MFACR)) regulates mitochondrial fission and apoptosis in the heart by directly targeting and downregulating miR-652-3p; this in turn blocks mitochondrial fission and cardiomyocyte cell death by suppressing MTP18 translation. MTP18 deficiency reduces mitochondrial fission and suppresses cardiomyocyte apoptosis and MI. miR-652-3p directly downregulates MTP18 and attenuates mitochondrial fission, cardiomyocyte apoptosis, and MI in vitro and in vivo. MFACR directly sequesters miR-652-3p in the cytoplasm and inhibits its activity. MFACR knockdown in cardiomyocytes and mice attenuates mitochondrial fission and MI. Our results reveal a crucial role for circRNA in regulating mitochondrial dynamics and apoptosis in the heart; as such, circRNAs may serve as a potential therapeutic avenue for cardiovascular diseases.