Alzheimer’s disease (AD) is a brain disease characterized by gradual memory loss and cognitive impairments. Acetylcholinesterase (AChE) inhibitors—such as donepezil, memantine, and tacrine—are FDA-approved medications for AD treatment. Due to the lack of their efficacy and higher side effects, many researchers have been searching for effective and safer alternatives. In this study, experimentally proved phytochemicals against brain diseases were screened based on their binding energies to the target site of AChE, pharmacokinetic properties, and drug-likeness. Although some phytochemicals showed higher binding affinities than the control drug (donepezil), they did not show permeability across the blood-brain barrier (BBB). However, berberine, anthocyanin, and diterpene alkaloid can cross the BBB and showed good binding affinities of −10.3, −10.1, and −10.2 kcal/mol, respectively. MD simulation and PCA of the simulation data of the protein and protein-ligand complexes proved that the complexes are stable in the biological environment. A total of 16 derivatives of berberine and 3 derivatives of anthocyanin also showed higher binding energies compared to the binding affinity (−11.5 kcal/mol) of the donepezil. The derivatives were designed by substituting –F, –CF3, –CN, and –NH2, and provided higher docking scores due to increasing of nonbonding interactions. MM/GBSA calculations show that the binding free energies of the best predicted derivatives of diterpene alkaloid, anthocyanin, and berberine (DA22, AC11, and BB40) are −100.4 ± 8.4, −79.3 ± 8.7, and −78.3 ± 10.7 kcal/mol, respectively, with the protein. Overall, this study was successful in finding new, highly effective, and possibly safer inhibitors of AChE. Communicated by Ramaswamy H. Sarma. © 2023 Informa UK Limited, trading as Taylor & Francis Group.