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Indirubin-3′-monoxime is an effective inhibitor of cyclin-dependent protein kinases, and may play an obligate role in neuronal apoptosis in Alzheimer′s disease. Here, we found that indirubin-3′-monoxime improved the morphology and increased the survival rate of SH-SY5Y cells exposed to amyloid-beta 25-35 (Aβ25-35 ), and also suppressed apoptosis by reducing tau phosphorylation at Ser199 and Thr205. Furthermore, indirubin-3′-monoxime inhibited phosphorylation of glycogen synthase kinase-3β (GSK-3β). Our results suggest that indirubin-3′-monoxime reduced Aβ25-35 -induced apoptosis by suppressing tau hyperphosphorylation via a GSK-3β-mediated mechanism. Indirubin-3′-monoxime is a promising drug candidate for Alzheimer′s disease.