Long pepper ( Piper longum L.) and black pepper ( Piper nigrum L.) plants are commonly used as spices around the world and have also been postulated to have medicinal effects. Piperine, as the major alkaloid of P. nigrum and P. longum , has gained wide attention of the medical community and culinary enthusiasts. This study seeks to determine the effects of piperine on neuronal apoptosis in peri‐infarcted cerebral cortices of rats with permanent middle cerebral artery occlusion (pMCAO) injury. Evaluation of the different behavioral components was conducted after pMCAO. 2, 3, 5‐Triphenyltetrazolium chloride (TTC) was used to evaluate the area of cortical ischemia. Gross histopathological changes, as well as microscopic neuronal changes, were observed in brain tissue samples. The protein expression of Caspase‐3, Caspase‐9, Bax, Bcl‐2, and Cytochrome C (Cyt‐c) was analyzed using western blotting. The findings reveal that rats that received piperine treatment show markedly decreased neurological deficit, less ischemia‐induced cellular damage, as well as smaller areas of cerebral infarction, with less severe macro and microcellular cerebral structural changes. Western blotting analysis reveals that piperine administration inhibits Bax, while enhancing Bcl‐2 expression. The protein expression of Caspase‐3, Caspase‐9, and Cyt‐c was also found to be significantly inhibited. We conclude that piperine may provide several beneficial neuroprotective effects that warrant further investigation.