New N ‐allyl/propargyl 4‐substituted 1,2,3,4‐tetrahydroquinolines derivatives were efficiently synthesized using acid‐catalyzed three components cationic imino Diels–Alder reaction (70–95%). All compounds were tested in vitro as dual acetylcholinesterase and butyryl‐cholinesterase inhibitors and their potential binding modes, and affinity, were predicted by molecular docking and binding free energy calculations (∆G) respectively. The compound 4af ( IC 50 = 72 μ m ) presented the most effective inhibition against acetylcholinesterase despite its poor selectivity ( SI = 2), while the best inhibitory activity on butyryl‐cholinesterase was exhibited by compound 4ae ( IC 50 = 25.58 μ m ) with considerable selectivity ( SI = 0.15). Molecular docking studies indicated that the most active compounds fit in the reported acetylcholinesterase and butyryl‐cholinesterase active sites. Moreover, our computational data indicated a high correlation between the calculated ∆ G and the experimental activity values in both targets.