Ischemia is defined as the insufficiency of blood flow to a local area due to an obstruction within the blood vessels supplying the affected area. Ischemia-induced neuronal loss is a key feature in various common neurological disorders, such as migraine with aura, stroke, and epilepsy disorders, which are often comorbid. Despite the various clinical presentations of these disorders, they also share common pathological mechanisms, including impaired cerebral blood flow, neuronal depolarization, and ultimately neuronal loss. Therefore, this chapter aims to describe how ischemia influences survival and functionality of neurons across these disorders. We also summarize the most utilized animal models of stroke, migraine, and epilepsy, with particular focus on the model induction and evaluation and the underlying mechanisms represented by spreading depolarizations and cortical spreading depression, which are fundamental processes between ischemia and neuronal loss.