Docosahexaenoic acid (DHA) has been studied for many years owing to its protective effect on the decline in brain function. DHA intake reduces the risk of Alzheimer's disease (AD) and decreases amyloid deposition; however, the underlying molecular mechanism has not been completed elucidated. In this study, the effect of DHA on the cognitive function of amyloid precursor protein (APP)/PS1 in wild-type mice and its related mechanism were investigated. Results from the Morris water maze test showed that DHA improved learning and memory function in mice. Moreover, DHA reduced neuronal damage in mice brains, as determined using Nissl staining. Unsaturated fatty acid levels in the brain of mice increased (p < 0.01) after DHA administration and saturated fatty acid levels decreased (p < 0.01). The deposition of amyloid-beta (Aβ) plaques and tau protein neurofibrillary tangles was significantly inhibited. The mechanism of action of DHA was attributed to the upregulation of the expression of β-secretase (BACE)2, which competed with BACE1 to cleave APP, thus decreasing the production of extracellular Aβ fragments (p < 0.01). The expression level of insulin-degrading enzyme was not significantly different. The expression of N-methyl-D-aspartate receptors was further downregulated and the phosphorylation of glycogen synthase kinase-3β and tau protein was inhibited (p < 0.01). These data indicated that DHA could protect cognitive function in mice by reducing Aβ plaque formation and decreasing tau phosphorylation levels.