Ischemic stroke is a major health concern and a leading cause of mortality worldwide. Oxidative stress is an early event in the course of stroke inducing neuro-inflammation and cell death. Grape seed extract (GSE) is a natural phytochemical mixture exhibiting antioxidant, anti-inflammatory and neuroprotective properties. Orlistat (ORL) is an anti-obesity agent and a gastro-intestinal lipase inhibitor which showed recently beneficial effects on brain lipotoxicity. Recent studies reported the increase of lipase activity upon stroke which led us to investigate the neuroprotective effect of ORL on rat brain I/R injury as well as the putative synergism with GSE. I/R insult infarcted the brain parenchyma as assessed by TTC staining, induced an oxidative stress as revealed by increased lipoperoxidation along with alteration of antioxidant enzymes activities which was corrected using the cotreatment of ORL + GSE. I/R also disturbed the main metabolic pathways involved in brain fueling as glycolysis, neoglucogenesis, glycogenolysis, TCA cycle and electron transfer chain (ETC) complexes. These disturbances were also corrected with the cotreatment ORL + GSE which maintained energetic activities near to the control level. I/R also disrupted transition metals distribution, along with associated enzymes as tyrosinase, LDH or glutamine synthetase activities and induced hippocampal inflammation as revealed by glycogen depletion from dentate gyrus area along with depressed anti-inflammatory IL1β cytokine and increased pro-inflammatory CD68 antigen. Interestingly almost all I/R-induced disturbances were corrected either partially upon ORL and GSE on their own and the best neuroprotection was obtained in the presence of both drugs (ORL + GSE) enabling robust neuroprotection of the sub granular zone within hippocampal dentate gyrus area.