Ischemic stroke has remained a principal cause of mortality and neurological disabilities worldwide. Blood flow resumption, reperfusion, in the cerebral ischemia prompts a cascade in the brain characterized by various cellular mechanisms like mitochondrial dysfunction, oxidative stresses, endoplasmic reticulum (ER) stress, and excitotoxicity, finally resulting in programmed cell death. Any changes in the ER-mitochondria axis are probably responsible for both the onset and progression of central nervous system diseases. Melatonin, a neurohormone secreted by the pineal gland, has antioxidative, anti-inflammatory, and anti-apoptotic properties. Most studies have shown that it exerts neuroprotective effects against ischemic stroke. It was observed that melatonin therapy after the stroke not only leads to reduce mitochondrial dysfunction but also cause to alleviate ER stress and inflammation. This review discusses the impact of melatonin on mitochondrial, ER function, and on the crosstalk between two organelles as a therapeutic target for stroke. Given that the influences of melatonin on each organelle separately, its effects on mechanisms of crosstalk between ER and mitochondria are discussed.