Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion (I/R) injury, suggesting a novel pharmacological strategy for cardioprotection. The study shows that modulating mitochondrial morphology, specifically by promoting mitochondrial fusion, reduces cell death and protects against I/R injury. In HL-1 cells, overexpression of mitochondrial fusion proteins (Mfn1, Mfn2) or a dominant-negative mutant of Drp1 (Drp1K38A) increased mitochondrial elongation, decreased mitochondrial permeability transition pore (mPTP) sensitivity, and reduced cell death after simulated I/R injury. Pharmacological inhibition of Drp1 with mdivi-1 replicated these effects. In adult murine cardiomyocytes, mdivi-1 treatment reduced cell death and inhibited mPTP opening after I/R injury. In vivo treatment with mdivi-1 reduced myocardial infarct size in mice subjected to coronary artery occlusion and reperfusion. The study also identified elongated mitochondria in adult rodent hearts, and in vivo treatment with mdivi-1 increased the proportion of elongated mitochondria. These findings suggest that inhibiting mitochondrial fission may be a promising therapeutic approach for cardioprotection. The study highlights the importance of mitochondrial morphology in cardiac protection and suggests that targeting mitochondrial dynamics could be a novel strategy for treating I/R injury.Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion (I/R) injury, suggesting a novel pharmacological strategy for cardioprotection. The study shows that modulating mitochondrial morphology, specifically by promoting mitochondrial fusion, reduces cell death and protects against I/R injury. In HL-1 cells, overexpression of mitochondrial fusion proteins (Mfn1, Mfn2) or a dominant-negative mutant of Drp1 (Drp1K38A) increased mitochondrial elongation, decreased mitochondrial permeability transition pore (mPTP) sensitivity, and reduced cell death after simulated I/R injury. Pharmacological inhibition of Drp1 with mdivi-1 replicated these effects. In adult murine cardiomyocytes, mdivi-1 treatment reduced cell death and inhibited mPTP opening after I/R injury. In vivo treatment with mdivi-1 reduced myocardial infarct size in mice subjected to coronary artery occlusion and reperfusion. The study also identified elongated mitochondria in adult rodent hearts, and in vivo treatment with mdivi-1 increased the proportion of elongated mitochondria. These findings suggest that inhibiting mitochondrial fission may be a promising therapeutic approach for cardioprotection. The study highlights the importance of mitochondrial morphology in cardiac protection and suggests that targeting mitochondrial dynamics could be a novel strategy for treating I/R injury.