Cardiovascular toxicity induced by natural toxins represents a critical area of research due to the potentially fatal consequences of toxin exposure on heart function. Natural toxins, derived from diverse sources such as animals, plants, bacteria, algae, fungi and mushrooms, exert significant effects on the cardiovascular system by targeting ion channels, disrupting cardiac cell membranes, and altering intracellular ion homeostasis. These interactions can lead to severe outcomes, including arrhythmias, myocardial ischemia, and heart failure. However, many natural toxins have been repurposed for therapeutic uses, serving as drugs, in vaccine production, and as tools for biomedical research. This chapter provides a comprehensive overview most of the natural toxins affecting heart function, their targets in the heart tissue, most important mechanisms of cardiovascular toxicity and clinical manifestations, as well as and treatment strategies for managing natural toxin poisoning.