Stroke is a serious acute cerebrovascular disease attributable to disruptions in the blood supply to the brain tissue as a result of vascular obstruction or sudden rupture of blood vessels in the brain, which further result in hypoxia of the brain and reduction of necessary nutrients, apoptosis of neurons, and damage to brain tissue. The majority of stroke patients are ischemic stroke. The main clinical treatments for ischemic stroke include medical thrombolysis in the early stage of onset and surgical thrombectomy or stent implantation in the late stage of onset, all of which have their own indications, advantages, and disadvantages, and show limited clinical application. For cerebral ischemia-reperfusion injury with an extremely poor prognosis, there is currently no effective prevention and treatment method in the clinic. Therefore, timely and effective treatment is needed to treat cerebral ischemia-reperfusion injury. An increasing number of studies have shown that natural products have a good curative effect on cerebral ischemia-reperfusion injury. However, due to their low solubility, low bioavailability, and short half-life, many natural products cannot optimally exert their curative effects on cerebral ischemia-reperfusion injury. Natural products-based nanoparticles modified with specific ligands have attracted much attention because of their high-efficiency permeation through the blood–brain barrier, targeted delivery abilities, and the protection of the active components from degradation. Therefore, this review focused on the prevention and treatment of cerebral ischemia-reperfusion injury in the natural product-based nanoparticles.