With the aid of density functional theory (DFT) calculations, we have performed a detailed mechanism study for the catalytic cycloisomerization reactions of propargylic 3-indoleacetate to better understand the observed divergent reactivities of two catalysts, PtCl₂ and (PPh₃)AuSbF₆, which result in [3 + 2]- and [2 + 2]-cycloaddition products, respectively. The calculated results confirm that the lactone intermediates are common and necessary species for the formation of the two products and that PtCl₂ and (PH₃)AuSbF₆ respectively favor the formation of the [3 + 2]- and [2 + 2]-products. The intrinsic reasons for the divergent reactivities of the two catalysts have been analyzed in detail. We believe that the essentially different metal–ligand interactions in PtCl₂ and (PPh₃)AuSbF₆ are mainly responsible for their divergent regioselectivities, while the solvent effects have little impact on the catalyst activity. Starting from lactone intermediates, PtCl₂ induces the intramolecular nucleophilic addition to give the [3 + 2] cycloisomerization product due to the strong π-electron-donating ability of chlorine ligands, while (PPh₃)AuSbF₆ results in the intramolecular nucleophilic addition reaction to form the [2 + 2] cycloisomerization product because of the strong σ-electron-donating ability of phosphine ligands.