The Alzheimer's disease (AD) is one of the common cognitive disorders in the elderly. AD shares some similar pathological characters with diabetes mellitus (DM), suggesting potential application of anti-diabetic agents, such as vanadyl complexes, in therapeutic treatment of AD. In the present work, we studied the effects of vanadyl acetylacetonate (VO(acac)2) and cinnamaldehyde (CA) on an AD model based on SH-SY5Y neural cells. The experimental results showed that VO(acac)2 at sub-micromolar concentrations could improve the viability of neural cells with or without increased β-amyloid (Aβ) burden; and the combination of VO(acac)2 and CA showed an additive cell protection effects. Further investigation revealed that for SH-SY5Y neural cells, VO(acac)2 could activate PPART-AMPK signal transduction and inhibit GSK 3β, one of the major kinases for Tau hyperphosphorylation. Meanwhile, CA could correct the abnormal mitochondrial morphology due to Aβ-induced excessive mitochondrial fission, thus restoring/enhancing the mitochondrial function. In addition, both VO(acac)2 and CA decreased intracellular reactive oxygen species (ROS) level and inhibited formation of toxic Aβ oligomers. Overall, VO(acac)2 might work with CA in improving the neural cell viability under the Aβ burden, suggesting application of vanadium metallodrugs in AD treatment.