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Ischemic stroke (IS) is a rapidly increasing global burden and is associated with severe neurological decline and mortality. There is urgent requirement of the efforts, aimed to identify therapeutic strategies that are effective in clinic to promote significant recovery from IS. Studies have shown that mitochondria mediated neuroprotection can be a competent target against ischemic damage. Therefore, we examined whether mitochondrial impairment is regulated by Piperine (PIP), an alkaloid of Piper Longum , which has neuroprotective activity against ischemic brain injury. In this study, transient middle cerebral artery occlusion (tMCAO) surgery was performed on male Wistar rats for 90 min followed by 22.5 h of reperfusion for mimicking the IS condition. This study consisted of three groups: sham, tMCAO and tMCAO + PIP (10 mg/kg b.wt., p.o/day for 15 days), and studied for behavioral tests, infarct volume, brain pathological changes, mitochondrial dysfunction, inflammation alongwith cell survival status. PIP pre-treatment showed reduction in neurological alterations and infarct volume. In addition, PIP pre-treatment suppressed the mitochondrial dysfunction and might have anti-apoptotic potential by preventing Cytochrome c (Cyt c) release from mitochondria to cytoplasm and caspase 3 activation. It also regulates pro-apoptotic, Bax and anti-apoptotic, Bcl-2 proteins accompanied by glial fibrillary acidic protein (GFAP) positive cells in cortex region. Quantitative Reverse transcription-polymerase chain reaction (qRT-PCR) results also showed that PIP reduced the expression of pro-inflammatory protein, interleukin-1 β (IL-1β) and enhanced cell survival by restoring the activity of brain derived neurotrophic factor (BDNF) and its transcription protein, cAMP response element binding protein (CREB). Taken together, PIP reduced the mitochondrial dysfunction, neurological impairment, and enhanced neuronal survival. In conclusion, our findings reinforce PIP as an effective neuroprotective agent and provide important evidence about its role as a potential target to serve as a promising therapy for treatment of IS. Schematic representation of mitochondria mediated mechanisms of neuroprotection against ischemic stroke provided by Piperine. Piperine can inhibit mitochondrial dysfunction by suppressing inflammation and mitochondrial ROS mediated alterations in ETC and reduced mitochondrial membrane permeability (Δѱm) thereby preserving mitochondrial Cyt c level through blockage of mitochondrial permeability transition pore (mPTP). Finally, it might increase anti-apoptotic (Bcl-2) protein and decrease pro-apoptotic (Bax) protein, and alleviated neuronal cell death. Piperine also involved in cell survival processes and ultimately rescued neuronal morphological alterations and neurobehavioral abnormalities. IL-1β (Interleukin-1β), GFAP (Glial Fibrillary Acidic Protein), LPO (Lipid Peroxidation), GSH (Glutathione), Cyt c (Cytochrome c), Electron transport chain (ETC), Reactive oxygen species (ROS). [Display omitted] • Ischemic animals pre-treated with piperine showed reduced neurological alterations and infarct volume. • Piperine improved mitochondrial dysfunction. • Piperine showed anti-apoptotic potential by preventing cytochrome c release from mitochondria to cytoplasm. • PIP reduced neurological impairment and enhanced cell survival. [ABSTRACT FROM AUTHOR]