In this study, a series of N‐substituted‐(p‐tolyl)pyridazin‐3(2H)‐one derivatives were synthesized and evaluated for their AChE inhibitory activity. The chemical structures of novel compounds 5(a–m) were confirmed by 1H‐NMR, 13C‐NMR, IR and HRMS analysis. In order to eliminate the symptomatic effects of Alzheimer's disease, the proposed compounds were evaluated by acetylcholinesterase inhibition activity study in accordance with the cholinergic hypothesis. The results revealed that the N‐substituted‐(p‐tolyl)pyridazin‐3(2H)‐one derivatives inhibited the enzymes significantly. Ki values for acetylcholinesterase in the range of 0.56±0.15–4.12±1.42 μM. Compound 5 h demonstrated the greatest in AChE activity compared with tacrine (0.56±0.15 μM). Molecular docking studies were performed for all compounds that compared tacrine in AChE activity in‐vitro. As a result of molecular docking studies (ΔGBind, docking score, XP Gscore, Glide energy, Glide emodel), 5 f, 5 g and 5 h compounds showed good inhibitory properties in the AChE active site as in silico.