Introduction: Amyloid-β (Aβ) peptides play a key role in the pathogenesis of Alzheimer disease and exert various toxic effects on neurons. Dietary phytochemicals are currently used as an adjuvant therapy to accelerate their therapeutic efficacy. Therefore, the present study was designed to investigate the effect of curcumin and its co-administration with piperine against Aβ42 induced cytotoxicity, fibril aggregation and oxidative damage in SH-SY5Y cells. Methods: The neuroblastoma SH-SY5Y cells were cultured with different treatments of Aβ42, individual curcumin and piperine and combination of curcumin and piperine. Cell viability, Aβ fibril aggregation and oxidative damage such as lipid peroxidation, catalase and glutathione were assessed. The abilities of curcumin and its combination, piperine to scavenge free radicals and to inhibit Aβ aggregation and β-sheeted formation were further assessed. Results: Curcumin and piperine preserves cell viability, which is decreased by Aβ, indicate that curcumin protects Aβ-induced neuronal damage. Under aggregating conditions in vitro, curcumin and piperine inhibited aggregation as well as disaggregated fibrillar Aβ42, indicating favorable stoichiometry for inhibition. Results also showed that curcumin and piperine as a combination was a better Aβ42 aggregation inhibitor than the individual compounds. Curcumin and piperine depresses Aβ-induced up-regulation of neuronal oxidative stress. The ability of these compounds to scavenge free radicals and inhibit the formation of Aβ aggregation are implicated from the results of this study. Conclusion: This combination of curcumin and piperine shows a more protective effect on neuronal oxidative damage when they was added into cultured neurons not later than Aβ, especially prior to Aβ. The curcumin and piperine combination prevents neurons from Aβ-induced oxidative stress, indicating a promising therapeutic in preventive medicine for Alzheimer disease.