Ischemic heart disease is a myocardial disorder stemming from coronary atherosclerosis. Treatment methods encompass thrombolysis, interventional surgery, and coronary artery bypass grafting. However, restoring blood supply to the damaged region can exacerbate myocardial injury, leading to myocardial ischemia-reperfusion(I/R) injury . Mitochondria and endoplasmic reticulum (ER) represent interconnected membrane systems crucial for energy metabolism, signal transduction, and cell death. The unfolded protein response in cardiac cells maintains ER equilibrium, while mitochondrial dysfunction also contributes to myocardial injury associated with I/R. This review comprehensively outlines the roles of ER and mitochondria in regulating I/R injury in cardiac cells, with a focus on the targeted mechanisms of natural compounds and small molecules.