An unprecedented silver-catalyzed desulfurizative annulation of 1,2-benzisothiazoles with ynamides is disclosed, which offers a concise protocol to access multi-substituted isoquinoline derivatives. Mechanistically, the occurrence of the chemo- and regio-selective N-attack of 1,2-benzisothiazoles on the alkynyl carbon connected with the amide moiety of ynamides is more feasible, according to DFT calculations. Subsequently, the generated adduct could undergo S–N bond cleavage followed by annulation to give a [5 + 2] intermediate. Driven by aromatization, an S-atom extrusion step could proceed to afford the final isoquinoline derivative product.