BACKGROUND Cognitive decline (e.g., memory loss), which mainly occurs in the elderly, is termed dementia. In the present study, we intended to explore the cholinesterase inhibitory activity of some novel synthesized chalcones, together with their effect on β-amyloid anti-aggregation. MATERIAL AND METHODS A novel class of chalcone derivatives have been synthesized and characterized by FT-IR, ¹H-NMR, ¹³C-NMR, and mass and elemental analysis. These derivatives were later used for the determination of acetylcholinesterase (AChE) inhibitory and b-amyloid anti-aggregation activity. RESULTS The results of the study showed that among the developed compounds, 8g inhibits AChE more prominently than BuChE, as suggested by a selectivity index (SI) of 2.88. Furthermore, the most potent compound, 8g, showed considerable action in inhibition of β-secretase and Aβ aggregation, but not as prominent as that of curcumin as a standard. CONCLUSIONS In conclusion, our study revealed a novel class of chalcone derivatives as a selective inhibitor of AChE with considerably action against β-secretase and Aβ aggregation. Our results may be useful in developing AD drug therapy and warrant further investigation to generate more advanced analogues.