A short and efficient two-step total synthesis of marine-derived bis-indole alkaloid fascaplysin starting from commercially available tryptamine in 68% overall yield is reported. A key step involved in the present strategy is tandem dehydrative condensation between ortho-halo substituted glyoxal with tryptamine followed by dehydrogenation. Fascaplysin inhibited acetylcholinesterase (AChE) in non-competitive manner with IC50 and ki values of 1.49 and 2.28 μM respectively and with 60-fold selectivity for AChE versus butyrylcholinesterase. Molecular docking studies revealed that fascaplysin accommodates within a peripheral anionic site and inner linings of the AChE active site gorge.