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Alzheimer’s disease is a common degenerative disease which has a great impact on people’s daily lives, but there is still a certain market gap in the drug research about it. Palmatine, one of the main components of Huangteng, the rattan stem of Fibraurea recisa Pierre (Menispermaceae), has potential in the treatment of Alzheimer’s disease. The aim of this study was to evaluate the neuroprotective effect of palmatine on amyloid beta protein 25–35-induced rat pheochromocytoma cells and AD mice and to investigate its mechanism of action. CCK8 assays, ELISA, the Morris water maze assay, fluorescent probes, calcein/PI staining, immunofluorescent staining and Western blot analysis were used. The experimental results show that palmatine can increase the survival rate of Aβ25-35-induced PC12 cells and mouse hippocampal neurons, reduce apoptosis, reduce the content of TNF-α, IL-1β, IL-6, GSH, SOD, MDA and ROS, improve the learning and memory ability of AD mice, inhibit the expression of Keap-1 and Bax, and promote the expression of Nrf2, HO-1 and Bcl-2. We conclude that palmatine can ameliorate oxidative stress and neuroinflammation produced by Aβ25-35-induced PC12 cells and mice by modulating the Nrf2/HO-1 pathway. In conclusion, our results suggest that palmatine may have a potential therapeutic effect on AD and could be further investigated as a promising therapeutic agent for AD. It provides a theoretical basis for the development of related drugs.