Docosahexaenoic acid-enriched phospholipids (DHA-PLs) are important bioactive components from marine foods, and are barely obtained by people living inland due to limited sources of commercial DHA-PLs compared to commercial DHA-TG and DHA-EE fish oil. Therefore, it is of significance to develop substitutions of DHA-PLs. In the present study, we comparatively investigated the effects of DHA-phosphatidylcholine (PC) and the recombination of DHA-ethyl ester (EE) with egg PC on improving the dysfunction of memory and cognition in senescence-accelerated prone 8 (SAMP8) mice and illustrated the possible underlying mechanisms. Results showed that DHA-PC exhibited stronger effects than the recombination of DHA-EE with egg PC on improving the dysfunction of memory and cognition via suppressing Aβ generation, neuro-inflammation and apoptosis, and improving neurotrophins. These findings suggested that DHA-PLs (DHA-PC) could not be substituted by the recombination of commercial fish oil with DHA-free PC in alleviating age-related memory loss and cognitive deficiency in SAMP8 mice, which provided a reference for the prevention and treatment of neurodegenerative diseases.