The present study was performed to investigate the protective effect of phytoceramide against ß-amyloid protein (Aβ) (25–35)-induced memory impairment and its underlying mechanisms in mice. Memory impairment in mice was induced by intracerebroventricular injection of 15 nmol Aβ (25–35) and measured by the passive avoidance test and Morris water maze test. Chronic administration of phytoceramide (10, 25 and 50 mg/kg, p.o.) resulted in significantly less Aβ (25–35)-induced memory loss and hippocampal neuronal death in treated mice compared to controls. The decrease of glutathione level and increase of lipid peroxidation in brain tissue following injection of Aβ (25–35) was reduced by phytoceramide. Alteration of apoptosis-related proteins, increase of inflammatory factors, and phosphorylation of mitogen activated proteins kinases (MAPKs) in Aβ (25–35)-administered mice hippocampus were inhibited by phytoceramide. Phosphatidylinositol 3′-kinase (PI3K)/Akt pathway and phosphorylation of cyclic AMP response element-binding protein (CREB) were suppressed, while phosphorylation of tau (p-tau) was increased in Aß (25–35)-treated mice brain; these effects were significantly inhibited by administration of phytoceramide. These results suggest that phytoceramide has a possible therapeutic role in managing cognitive impairment associated with Alzheimer’s disease. The underlying mechanism might involve inhibition of p-tau formation via anti-apoptosis and anti-inflammation activity and promotion of PI3K/Akt/CREB signaling process.