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Flavonoids are one of the most exciting types of phenolic compounds with a wide range of bioactive benefits. A series of flavone derivatives (<b>F1</b>–<b>F5</b>) were previously synthesized from substituted O-hydroxy acetophenone and substituted chloro-benzaldehydes. The titled compounds <b>F1</b>–<b>F5</b> in the present study were evaluated for their anticholinesterase potential (against AChE and BuChE). The obtained results were then validated through a molecular docking approach. Compound <b>F5</b> was found to be the most potent inhibitor of AChE (IC₅₀ = 98.42 ± 0.97 µg/mL) followed by compound <b>F4</b>, whereas compound <b>F2</b> was found to be the most promising inhibitor of BuChE (IC₅₀ = 105.20 ± 1.43 µg/mL) among the tested compounds. The molecular docking analysis revealed a similar trend in the binding affinity of compounds with the targeted enzymes and found them to be capable of forming highly stable complexes with both receptors. The selected compounds were further subjected to in vivo assessment of cognitive function in a scopolamine-induced amnesic animal model, in which almost all compounds <b>F1</b>–<b>F5</b> significantly attenuated the amnesic effects as evaluated through Y-Maze Paradigm and novel object discrimination (NOD) tasks, findings that were further supported by ex vivo experimental results. Among (<b>F1</b>–<b>F5</b>), <b>F5</b> showed significant anti-amnesic effects in scopolamine-induced amnesic models and ameliorated the memory loss in behavioral model studies as compared to counterparts. In ex vivo study, noteworthy protection from oxidative stress in the brains of scopolamine-induced amnesic mice was also recorded for <b>F5</b>. These findings also confirmed that there were no significant differences among the in vivo and ex vivo results after administration of <b>F1</b>–<b>F5</b> (7.5 or 15 mg/kg) or donepezil (2 mg/kg). These synthesized flavonoids could serve as potential candidates for new neuroprotective and nootropic drugs. However, further studies are needed to validate their observed potential in other animal models as well.