Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. Although its pathogenesis remains unclear, studies have indicated microglia-mediated neuroinflammation playing an important role. Phytosterols are a class of natural compounds presented in food, and have anti-inflammatory abilities. Recent studies suggested that phytosterols can traverse the blood-brain barrier and enter the brain, however, it remains largely unknown that whether phytosterols affect neuroinflammation in the AD pathogenesis. Here, we used APP_swe/PS1_dE9 mice as the animal model of AD, and found that stigmasterol treatment attenuated cognitive deficits, and decreased Aβ₄₂ concentration in cortex and hippocampus. Stigmasterol treatment also suppressed neuroinflammation, by reducing pro-inflammatory cytokine levels and microglia activation. Next, we simulated BV2 cells with Aβ₄₂ oligomers, which induced inflammatory responses of microglia. Stigmasterol protected BV2 cells against Aβ₄₂ oligomers induced inflammation, and mediated secretion of pro-inflammatory cytokines via NF-κB and NLRP3 signaling pathways by AMPK activation. Stigmasterol also alleviated the M1 polarization of BV2 cells. In general, our study demonstrates that stigmasterol ameliorated neuroinflammation in APP/PS1 mice, and suppressed inflammatory response of microglia to Aβ₄₂ oligomers via AMPK/NF-κB and AMPK/NLRP3 signaling, which provides a mechanistic insight for stigmasterol in anti‐inflammation and AD therapy.