Aim: The aim of the present study was to investigate the protective effect of compound N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide (compound FLZ), a novel synthetic ana-logue of nature squamosamide, on Aβ25-35-induced toxicity and its active mecha-nism in human neuroblastoma SH-SY5Y cells. Methods: SH-SY5Y cells were pre-incubated with various concentrations of compound FLZ for 30 min and then cultivated with Aβ25-35 (25 μmol/L) for 48 h to induce neurotoxicity. Cell viability, lactate dehydrogenase (LDH) release, and the glutathione (GSH) level were deter-mined by a biochemical analysis. The cell apoptotic ratio and intracellular reactive oxygen species (ROS) level were measured by a flow cytometry analysis. The expression of apoptosis protein (Bcl-2 and Bax) and cytochrome c release were assayed by the Weste blot method. Results: The pretreatment of SH-SY5Y cells with FLZ (1 and 10 μmol/L) markedly increased cell viability and decreased LDH release and morphological injury. Also, FLZ attenuated the Aβ25-35-induced apoptotic cell ratio, regulated the apoptosis protein (Bcl-2 and Bax) expression, and decreased the cytochrome c release from mitochondria. FLZ also signifi-cantly inhibited the generation of ROS and the depletion of GSH induced by Aβ25-35 in SH-SY5Y cells. Conclusion: FLZ has protective action against Aβ25-35-in-duced toxicity in SH-SY5Y cells, which might be mediated through its antioxi-dant property.