<p>The present study investigates the therapeutic potential of Ranolazine in cerebral ischemic stroke, focusing on its neuroprotective properties in a middle cerebral artery occlusion/reperfusion (MCAO/R) induced ischemic brain injury in a rat model. Ranolazine demonstrated neuroprotective effects by reducing infarct size and brain edema, improving cerebral blood flow, and preserving blood-brain barrier integrity, leading to improved neurological function. Mechanistically, ranolazine decreased HIF-1α and GFAP expression while enhancing BDNF levels. Ranolazine increased mitochondrial complex enzyme activities (I, II, IV, and V) and enhanced the expression of the mitochondrial Tu translation elongation factor (TUFM), NRF1, and PGC-1α levels, indicating improved mitochondrial biogenesis and decreased mitochondrial oxidative stress markers such as 4-HNE and increased catalase and SOD. Further, ranolazine treatment reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 while increasing the anti-inflammatory cytokine IL-10, suggesting its anti-inflammatory potential in mitigating the stroke-associated neuroinflammation. Moreover, ranolazine suppressed apoptosis by reducing the levels of apoptotic mediators such as cytochrome c, caspase-9, and caspase-3, and flow cytometry analysis revealed a significant decline in neuronal apoptosis, which further underscores its neuroprotective efficacy. Therefore, the novelty of this research lies in demonstrating that ranolazine exerts neuroprotective effects against ischemic brain injury by simultaneously modulating apoptotic pathways, restoring vital neurological factors (BDNF, TUFM, NRF-1, PGC-1α), improving mitochondrial function, reducing oxidative stress, and attenuating neuroinflammation, offering a novel multi-targeted therapeutic approach, meriting further clinical studies.</p> Graphical Abstract <p></p>