Neurotoxicity of amyloid β (Aβ) plays an important role in Alzheimer's disease (AD) pathogenesis. In the present study, we investigated the comparative effects of docosahexaenoic acidphosphatidylcholine (DHA-PC) and docosahexaenoic acid-phosphatidylserine (DHA-PS) on Aβ-induced AD rats and studied further protective mechanisms underlying their effects. The administration of DHA-PC and DHA-PS (300 mg/kg, i.g., 27 days) had no effect on brain DHA levels but significantly improved Aβ-induced cognitive deficiency. Further mechanism research indicated that both DHA-PC and DHA-PS alleviated Aβ-induced neurotoxicity including oxidative stress, apoptosis, the neuroinflammation cascade, and hyper-phosphorylated tau. These results suggest that DHA-PC and DHA-PS represent a potential novel therapeutic candidate for the treatment of neurodegenerative diseases such as AD. Such an effect uncoupled with an increase in brain DHA but has an intimate relationship with the phospholipid polar groups, and DHA-PS has a particular advantage.