The mechanisms of brain damage during occurrence and development of ischemic stroke are related to energy metabolism disorders, acidosis, oxidative stress, inflammatory reactions, blood–brain barrier disruption, brain oedema, cell apoptosis, excitotoxicity, and calcium overload. Coenzyme I, namely nicotinamide adenine dinucleotide (NAD), is the central coenzyme of redox reactions and a key regulator of anti-stress and longevity. During the onset of ischemic stroke, NAD+ levels decrease, leading to dysfunction of the nucleus and mitochondria. Studies suggest that supplementing NAD+ and its precursors to restore NAD+ levels is a potential strategy for treating ischemic damage. Enzymes-regulating NAD+ synthetic metabolism, including nicotinamide phosphoribosyltransferase (NAMPT) and nicotinamide mononucleotide adenylyltransferases (NMNATs), are also potential targets for the treatment of ischemic stroke. Furthermore, some studies have identified NAD+-dependent enzymes such as sirtuins as promising therapeutic targets for ischemic stroke.