NADPH, the reductive coenzyme II, exhibits promising short- and long-term therapeutic effects in experimental ischemic stroke models. It significantly reduces the infarct volume in stroke models involving mice and rats, enhances survival rates post-stroke, and facilitates neural function recovery. The mechanism of action primarily involves suppressing mitochondrial dysfunction, neuronal inflammation, and regulating of autophagy. Additionally, it protects the blood–brain barrier and modulates platelet function. NADPH boasts a relatively wide treatment window, low acute toxicity, and minimal risk of intracerebral hemorrhage, representing a significant clinical advantage. Preliminary research has revealed beneficial effects of NADPH in hemorrhagic stroke models, indicating its potential as a candidate for cerebral ischemia treatment. The combination of NADPH and NOX inhibitors offers potent anti-inflammatory and neuroprotective benefits, and the concurrent use of NAD+ and NADPH may herald a novel therapeutic approach for ischemic stroke.