Abstract Increasing evidence suggests that the inappropriate activation of cyclin-dependent kinases (CDKs) could induce neuronal apoptosis in Alzheimer's disease (AD), which means that the pharmacological inhibitors of cell-cycle progression may effectively impede the development or progression of AD. Indirubin-3′-monoxime (IMX), a known effective inhibitor of CDKs, has been shown to have therapeutic effects on learning and memory deficits induced by beta-amyloid (Aβ) intracerebroventricular infusion in rats. In the present study, we investigated the neuroprotective effects of IMX on Aβ25–35-induced neuronal apoptosis and its potential mechanisms in human neuroblastoma SH-SY5Y cells. Aβ25–35-induced apoptosis, characterized by decreased cell viability, neuronal DNA condensation, and fragmentation, was associated with an increase in tau protein hyperphosphorylation. IMX, however, attenuated Aβ25–35-induced cell death in a dose-dependent manner. Furthermore, expression of hyperphosphorylation tau protein was significantly decreased with IMX treatment. Our study suggests that IMX may usefully prevent or delay the neuronal loss of AD.