Background: Hyperthyroidism is known to increase the risk of ischemic heart diseases. Octreotide has been reported to attenuate ischemia/reperfusion (I/R) injury. Whether it is useful when ischemic heart disease is accompanied with co-morbidities like hyperthyroidism needs more clarifying. So, this study aimed to explore the effect of octreotide on cardiac I/R injury in hyperthyroid rats and to clarify if Nrf2 activation is involved in this effect. Forty adult female Wistar rats were subdivided into control (euthyroid) (n = 10) and hyperthyroid (n = 30) groups. Rats in hyperthyroid group received L-thyroxine (12 mg/L) in drinking water for 35 days, then were randomly divided into three equal subgroups (n = 10): hyperthyroid control positive group, hyperthyroid octreotide treated group, and hyperthyroid octreotide + Nrf2 inhibitor (brusatol) treated group. Isolated hearts were submitted to I/R and evaluated for cardiac hemodynamics and infarct size. Serum T3 and T4, coronary efflux lactate dehydrogenase (LDH) and creatine kinase-myoglobin binding (CK-MB) and cardiac tissue malondialdehyde (MDA) were estimated. Nrf2- regulated gene expressions of HO-1, SOD, GPx, and catalase were assessed. Results: Octreotide administration to hyperthyroid rats improved baseline and post-ischemic recovery of cardiac hemodynamics, decreased the high coronary efflux LDH and CK-MB and tissue MDA, reduced infarction size, and upregulated the decreased antioxidative enzymes HO-1, SOD, GPx, and catalase mRNA expressions in the hyperthyroid I/R rat hearts. The Nrf2 inhibitor brusatol reversed the cardioprotective effect of octreotide in hyperthyroid I/R rat hearts. Conclusion: Octreotide can reduce oxidative stress to effectively alleviate I/R injury in the hyperthyroid rat hearts through upregulation of Nrf2-dependent antioxidative signaling pathways.