Oxidative stress (OS) and neuroinflammation are related to the pathogenic mechanism of Alzheimer's disease (AD). γ-Mangostin, a xanthone derivative obtained from mangosteen pericarp, could prevent their detrimental effects in AD.This study focused on determining the role of γ-mangostin in protection against the amyloid-β (Aβ) 42 oligomers-induced OS and inflammation in microglial BV2 cells and investigating their precise mechanism of action.Lactate dehydrogenase release assay and cell counting kit-8 assay were used to estimate the drug impact in BV2 cells and functional effects of the conditioned medium (supernatant of Aβ42 oligomers-/γ-mangostin-treated BV2 cells) on neuron-like SH-SY5Y and N2a cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay were carried out for detecting inflammatory factor contents. In addition, nitric oxide (NO) assay, an intracellular reactive oxygen species (ROS) assay, and qRT-PCR were performed to measure OS. Western blotting was used to explore the influence of γ-mangostin on the mitogen-activated protein kinase (MAPK) pathway.γ-Mangostin alleviated Aβ42 oligomer-induced inflammation by decreasing the levels of interleukin (IL) -6, IL-1β, and tumor necrosis factor-α, while attenuating OS through decreasing ROS/NO generation, and suppressing cyclo-oxygenase-2 and inducible NO synthase expressions. γ-Mangostin protected N2a and SH-SY5Ycells against the BV2 cell supernatant-induced toxicity following Aβ42 oligomer exposure. Furthermore, γ-mangostin inhibited c-Jun NH2-terminal kinase and p38 MAPK pathway activation.This study demonstrated that γ-mangostin could attenuate OS and inflammation resulting from Aβ42 oligomers, which also protect neurons against toxic medium-induced injury, suggesting that it may exert a protective effect in AD.Copyright © 2022. Published by Elsevier B.V.