Glycogen synthase kinase (GSK)-3β mediates amyloid-beta (Aβ) and oxidative stress-induced neurotoxicity in neurodegenerative disorders. Natural products with antioxidant activity, such as Sargassum (S.) oligocystum may modulate GSK-3β enzyme and protect against Aβ-induced neurotoxicity. Therefore, we aimed to assess the neuroprotective effects of a methanolic extract of S. oligocystum against Aβ-induced neurotoxicity in the SH-SY5Y cells and the contribution of GSK-3β inhibition to the neuroprotective effects of the S. oligocystum extract. SH-SY5Y neuroblastoma cells were seeded in 96 well plates and incubated with Aβ (20µM) and the methanolic extract of S. oligocystum (40, 50, and 70μg/ml) for 24h. We measured cell viability using the MTT assay. Western blot method was used to measure the expression of the GSK-3β and phosphorylated (p)-GSK-3β protein levels. The data were analyzed using one-way analysis of variance (ANOVA) followed by the LSD test. Amyloid-beta (20µM) reduced neuronal cell viability compared with the control group. Addition of S. oligocystum extract at concentrations of 40, 50 and 70μg/ml decreased the neurotoxic effects of Aβ. The extract of S. oligocystum at a concentration of 70μg/ml also decreased the effects of Aβ on the GSK-3β protein level. The pGSK-3β protein levels in the S. oligocystum groups (40 and 70μg/ml) plus Aβ were lower than the Aβ-treated group. The methanolic extract of S. oligocystum protected SH-SY5Y cells from Aβ-induced neurotoxicity. The attenuation of the GSK-3β protein level may contribute to the neuroprotective effects of S. oligocystum extract.