BACKGROUND: Oligopeptides from sea cucumber eggs (SCEPs) are rarely studied for their neuroprotective effects. METHODS: Therefore, we prepared SCEPs via simulated gastrointestinal digestion and then administered them to an Alzheimer's disease (AD) mouse model via gavage. Behavior tests, gut-brain histopathology and fecal microbiota transplantation (FMT) experiments were conducted, and gut microbiota and metabolite short-chain fatty acids (SCFAs) were evaluated via 16sRNA gene sequencing and LC-MS. RESULTS: The results showed that both the SCEP and FMT groups experienced improvements in the cognitive impairments of AD and showed reduced levels of Aβ, P-Tau, GFAP, and NFL in the brain, especially in the hippocampus. SCEP remodeled the gut microbiota, increasing the relative abundances of and by 2.7- and 4.8-fold compared with the model at the genus level. In the SCEP and FMT treatments, four SCFA-producing bacteria obtained from gut microbiota profiling showed consistent trends, indicating that they may be involved in mediating the neuroprotective effects of SCEP. Mechanically, SCEP regulated the SCFA distribution in feces, blood, and the brain, greatly increased the content of SCFAs in the brain up to 2000 μg/mg, eased gut-brain barrier dysfunction, inhibited HDAC3 overexpression, and upregulated BDNF/NT3 levels. CONCLUSIONS: This study provides a promising candidate for preventing AD and a reference for applying SCEP.