Alzheimer's disease (AD) is the primary cause of dementia in older adults. Amyloid-beta (Aβ) and tau protein neurofibrillary tangles accumulate in the brain, leading to a progressive decline in memory, thinking, and behavior. Neuroinflammation and oxidative stress play a significant role in the development and progression of AD. Research has suggested that α-mangostin (α-MG), a compound found in mangosteen peels, may have anti-inflammatory, antioxidant, and neuroprotective properties, which could be beneficial in the context of AD. Further research is required to fully comprehend the therapeutic mechanisms of α-MG on AD and determine its potential as a treatment option. α-MG treatment significantly improves the viability of hNSCs exposed to Aβ and reduces caspase activity. Furthermore, this treatment is associated with a notable decrease in the expression of TNF-α and IL-1β. The treatment effectively restores alterations in the expression of IKK and NF-κB (p65) induced by Aβ, which are critical factors in the inflammatory response. Moreover, α-MG effectively reduces iNOS and COX-2 levels in Aβ-treated hNSCs, showcasing its potential therapeutic benefits. Treatment with α-MG protects hNSCs against Aβ-induced oxidative stress and effectively prevents the decrease in Nrf2 levels caused by Aβ. The treatment significantly enhances the activity and mRNA expression of Nrf2 downstream antioxidant target genes, including SOD-1, SOD-2, Gpx1, GSH, catalase, and HO-1, compared to Aβ-treated controls. α-MG significantly reduces tau and ubiquitin (Ub) aggregates, enhances proteasome activity, and increases the mRNA expression of HSF1, HSP27, HSP70, and HSP90 in Tau-GFP-expressed hNSCs. This study significantly improves our comprehension of the anti-inflammatory, antioxidative stress, and anti-aggregated effects of α-MG. These findings have potential therapeutic implications for developing treatments that could delay AD progression and promote healthy aging.