A new set of quinazolin-4-one–based chalcones was prepared from 3-(4-acetylphenyl)-2- methylquinazolin-4(3H)-one (1) via a base-catalyzed Claisen–Schmidt condensation with substituted aromatic aldehydes. Synthesis was conducted using either a conventional NaOH/EtOH protocol or a solvent-minimized mechanochemical grinding approach. The grinding method delivered chalcones 3a–j and 5 in improved yields (85–94%) within 15–25 min, compared with 65–72% over 12–20 h for the solution method. Product structures were verified by spectroscopic and elemental analyses. The anti-Alzheimer’s potential was investigated through molecular docking of the complete series to propose binding modes and prioritize candidates, followed by in vitro evaluation of the five top-ranked compounds (3e, 3f, 5, 3i, and 3 h) for AChE and BuChE inhibition relative to donepezil. In vitro assays revealed the following IC₅₀ values for the compounds against AChE and BuChE: 3e (0.751 ± 0.023 µg/mL for AChE, 0.108 ± 0.003 µg/mL for BuChE), 3f (1.283 ± 0.039 µg/mL for AChE, 0.383 ± 0.01 µg/mL for BuChE), and 5 (2.148 ± 0.066 µg/mL for AChE, 1.212 ± 0.04 µg/mL for BuChE). These values suggest that 3e was the most promising dual inhibitor, outperforming donepezil in both AChE and BuChE inhibition. Docking outcomes agreed with the experimental trends, supporting this scaffold as a promising platform for dual cholinesterase inhibition. In silico ADMET assessment further indicated drug-like characteristics with predicted high oral bioavailability, supporting further lead optimization for Alzheimer’s disease therapy.