This article reviews the cardioprotective effects of natural products against doxorubicin (DOX)-induced cardiotoxicity and ischemia-reperfusion (I/R) injury, focusing on the modulation of ion channels and oxidative stress. Both conditions share lethal pathophysiological pathways driven by the overproduction of reactive oxygen species (ROS) and intracellular calcium (Ca2+) overload, culminating in the opening of the mitochondrial permeability transition pore (mPTP) and cardiomyocyte apoptosis. Bioactive compounds-including polyphenols (such as quercetin and resveratrol), terpenes (such as geraniol and carvacrol), and alkaloids (such as berberine)-exert robust pleiotropic protection. These molecules directly modulate sarcolemmal and mitochondrial ion channels (such as Cav1.2, Nav1.5, and mKATP), stabilize the action potential duration (APD), and activate intracellular survival cascades (Nrf2, SIRT1, AMPK). Although preclinical trials demonstrate high efficacy, the clinical translation of these findings still faces structural challenges, such as low bioavailability, the need for phytochemical standardization, and safety-related risks. The use of biotechnological delivery systems and the exploration of synergies with conventional therapies consolidate secondary metabolites as invaluable and highly promising adjuvant tools for the structural and electrophysiological protection of the myocardium.