This study investigated the effects of post-treatment with kolaviron on a 2-Vessel Occlusion (2-VO) model of cerebral ischemia/reperfusion (I/R) injury in rats to ascertain its level of efficacy as a potential therapeutic agent for stroke. Male Wistar rats submitted to 30 min of bilateral common carotid artery occlusion and 24 h of reperfusion were treated with kolaviron (25–100 mg/kg) or 20 mg/kg quercetin immediately after reperfusion and 2 h post reperfusion. At the end of the period of reperfusion, animals were scored for motor and cognitive deficits. Brain relative weight and water content were determined. Cortices, striata and hippocampi were dissected and processed for estimation of markers of oxidative stress, inflammation, neurotransmitter dysregulation and excitotoxicity. In addition, assessment of hippocampal mitochondrial integrity and histopathological examination of the cortical, striatal and hippocampal regions were carried out. There was reversal of 2-VO ischemia/reperfusion (I/R) induced motor and cognitive deficits by kolaviron post-treatment. Post-treatment with kolaviron also attenuated I/R-induced oxidative stress, neuroinflammatory events, excitotoxicity as well as mitochondrial dysfunction in brain tissues. Histopathological findings showed amelioration of I/R-induced neuronal cell damage by kolaviron post-treatment. The results revealed the multi-target neurotherapeutic activity of kolaviron and suggest that it is a promising candidate for drug development against stroke.