Mangosteen‐ (Garcinia mangostana‐) based nutraceutical compounds have long been reported to possess multiple health‐promoting properties. The current study investigated whether mangosteen pericarp (MP) could attenuate cognitive dysfunction. First, we found that treatment with MP significantly reduced the cell death and increased the brain‐derived neurotrophic factor (BDNF) level in an organotypic hippocampal slice culture (OHSC). We then investigated the effects of age and MP diet on the cognitive function of male C57BL/6J (B6) mice. After 8‐month dietary supplementation, the MP diet (5000 ppm) significantly attenuated the cognitive impairment associated with anti‐inflammation, increasing BDNF level and decreasing p‐tau (phospho‐tau S202) in older B6 mice. We further applied MP dietary supplementation to triple transgenic Alzheimer’s disease (3×Tg‐AD) mice from 5 to 13 months old. The MP diet exerted neuroprotective, antioxidative, and anti‐inflammatory effects and reduced the Aβ deposition and p‐tau (S202/S262) levels in the hippocampus of 3×Tg‐AD mice, which might further attenuate the deficit in spatial memory retrieval. Thus, these results revealed that the multifunctional properties of MP might offer a promising supplementary diet to attenuate cognitive dysfunction in AD.