The present study was conducted to investigate the protective effect of phytoceramide against focal transient ischemic brain damage and the underlying mechanisms. Focal transient ischemic brain damage was produced in rats by occlusion of the middle cerebral artery for 2 h followed by 24 h of reperfusion (MCAO/reperfusion). Orally administered phytoceramide (10, 25, and 50 mg/kg) significantly reduced MCAO/reperfusion-induced brain infarction and edema as well as the development of behavioral disabilities in the animals. Depletion of glutathione levels and lipid peroxidation in brain tissue following MCAO/reperfusion was reduced by administration of phytoceramide. The expressions of phosphorylated extracellular signaling-regulating kinases/mitogen-activated protein kinase (p-ERK1/2 MAPK), inflammatory factors such as cyclooxygenase-2 and inducible nitric oxide synthase, and pro-apoptotic proteins Bax and caspase-3 were increased while the anti-apoptotic protein Bcl-2 was decreased in ischemic brain; these effects were significantly inhibited by treatment with phytoceramide. Furthermore, phytoceramide activated the phosphatidylinositol 3′-kinase (PI3K)/Akt pathway to prevent ischemic brain damage. These results suggest that phytoceramide may help prevent neurodegeneration caused by ischemic stroke due to its anti-oxidant, anti-apoptotic, and anti-inflammatory properties.