Amyloid beta peptide (Aβ) has been confirmed to be an essential reason of Alzheimer's disease (AD) for a long time. Ferroptosis is a newly recognized oxidative cell death mechanism, which is highly related to AD. Recently, tetrahydroxy stilbene glycoside (TSG) has been beneficial in alleviating learning and memory of AD and aged mouse model. Unfortunately, the underlying mechanisms between TSG and ferroptosis in AD are poorly understood. Herein, we investigated whether neural cells in cerebral cortex and hippocampus that were seriously afflicted in APP/PS1 mice might be vulnerable to ferroptosis. Treatment with non-toxic TSG dose-dependently resisted Aβ-caused cytotoxic death in neuronal cells by regulating ferroptosis related proteins and enzymes in APP/PS1 mice. TSG also alleviated cellular oxidative stress and inflammatory damage in response to Aβ by attenuating the levels of oxidation products. Importantly, TSG administration abrogated Aβ-caused brain damage, indicating that TSG rescued brain cells. Subsequently, TSG promoted the activation of GSH/GPX4/ROS and Keap1/Nrf2/ARE signaling pathways. Notably, markers related to ferroptosis including increased lipid peroxidation, enhanced neuroinflammation such as NLRP3, and also the expression of DMT1, ACSL4 and NCOA4, were reduced by TSG administration. In addition, TSG enhanced antioxidative stress via the upregulation of SOD, and the expression of FTH1, CD98 and xCT. Taken together, our data indicated a novel mechanism of TSG in reversing Aβ-caused injury through restoring mitochondrial function via several signaling pathways, implying a promising candidate against neurodegenerative diseases especially AD. Hence, TSG should be taken into consideration during treatment of AD in the future.Copyright © 2021 Elsevier B.V. All rights reserved.