Objectives: Stroke is a leading cause of distress, disability, and death worldwide. The goal of reperfusion therapy for acute ischemic stroke (AIS) is the restoration of cerebral blood flow (CBF). If initiated too late, however, reperfusion therapy may paradoxically exacerbate tissue injury. Beyond a critical period, restoration of CBF may amplify already deranged inflammatory, apoptotic, and metabolic processes, increasing neurologic damage. This study was conducted to evaluate how timing of reperfusion therapy affects inflammatory, apoptotic, and metabolic responses after AIS. Materials and Methods: A total of 49 male Sprague-–Dawley rats were divided into four groups, either subject to 2- or 4-h of middle cerebral artery occlusion (MCAO) before reperfusion, 24 h of MCAO with no reperfusion, or a control group. Seven rats from each group were used for histological assay and for Western Blotting, respectively. Results: Infarction volumes were slightly decreased in the 2- and 4-h ischemia groups compared to the permanent ischemia group (49.5%, 49.3%, and 53.1%, respectively). No significant variation in neurological deficit scores was observed when comparing 2- and 4-h ischemia groups to the permanent ischemia group. Glucose metabolism protein (GLUT1 and GLUT3) expression was increased in all ischemia groups compared to the control group (P < 0.05). Expression of pro-inflammatory proteins (tumor necrosis factor α, interleukin-1 β, intercellular adhesion molecule-1, and vascular cell adhesion protein-1 was significantly increased in all ischemia groups compared to the control group at 24 (P < 0.05). There was significantly increased expression of pro-apoptotic proteins (caspase-3, cleaved caspase-3, and Bax) and significantly reduced anti-apoptotic protein (Bcl-2) expression in all the ischemia groups compared to the control group at 24 h (P < 0.05). Nuclear factor kappa (NF-κB) expression was significantly increased in all ischemia groups compared to the control group at 24 h (P < 0.05). Conclusion: The results of this study displayed relationships between the timing of reperfusion therapy and the multiple pathways discussed. There is potential utility in exploring and targeting components of the post-AIS inflammatory, apoptotic, and metabolic responses for neuroprotection against AIS and reperfusion injury.