Lychee seed is a traditional Chinese medicine and has many beneficial effects such as modulation of blood sugar and lipids, antioxidation, antivirus and antitumor. Studies have indicated that type II diabetes mellitus (T2DM) and Alzheimer's disease (AD) share common biological mechanisms including insulin resistance, impaired glucose metabolism, β‑amyloid (Aβ) formation, oxidative stress and presence of advanced glycation end products (AGEs). The present study investigated the effects of lychee seed extract (LSE) on neuroprotection, cognitive function improvement and possible underlying mechanisms in a rat model of T2DM with cognitive impairment. We analyzed the chemical profile of LSE using a UHPLC‑SPD chromatogram and evaluated its effect on the improvement of spatial learning and memory of rats by a Morris water maze. The levels of glucose, insulin, Aβ, AGEs, Tau protein and acetylcholinesterase in the blood and/or hippocampus of rats were determined by blood‑glucose meter, radioimmunoassay, chemical chromatometry, enzyme‑linked immunosorbent assay (ELISA) and immunohistochemical analysis, respectively. Results demonstrated that LSE consists of eight major and around 20 minor ingredients, and it remarkably prevents neuronal injury and improves cognitive functions in T2DM rats. The levels of glucose, insulin, Aβ, AGEs and Tau protein were significantly increased in the blood and/or hippocampus of T2DM rats, while LSE remarkably decreased their levels compared to vehicle treatment (P<0.01). The possible mechanisms may be associated with IR improvement and decreased formations of Aβ, AGEs and Tau protein in the hippocampus of T2DM rats. LSE may be developed as the agent for the treatment of T2DM and/or AD clinically.