Abstract: Objective: To investigate the protective effects of 6′′′-feruloylspinosinon Aβ_1-42-induced SH-SY5Y cells injury. Methods: SH-SY5Y cells were pretreated with 6′′′-feruloylspinosin (1、5、10、20 and 40 μmol/L) for 2 h and then co-treated with 5 μmol/L of Aβ_1-42 for 24 h. Cell viability was measured by CCK-8 assay; cell morphology was observed by Calcein-AM/PI assay; intracellular reactive oxygen species, malonic dialdehyde level, Glutathione peroxidaseactivity and mitochondrial membrane potential level were detected by the kit; expression of apoptosis-related proteins: Bcl-xL/Bcl-2 associated death promoter, B-cell lymphoma/leukemia-2 were detected by Western Blotting. Results: 6′′′-feruloylspinosin could inhibit Aβ_1-42-induced apoptosis and improve cell viability (P<0.001); reduce intracellular reactive oxygen species (P<0.001) and malondialdehyde (P<0.01) levels; increase glutathione peroxidase activity (P<0.001); upregulate cell mitochondrial membrane potential level (P<0.001); regulate apoptosis-related protein expression (P<0.01). Conclusion: The results validated that 6′′′-feruloylspinosin had a protective effect on SH-SY5Y cells with Aβ_1-42-induced damage, and the mechanism was that 6′′′-feruloylspinosin could alleviate oxidative damage and regulate the expression of apoptosis related proteins.