The rapid synthesis of natural-product-like polycycles presents significant synthetic challenges, often necessitating elaborate efforts or the use of noble-metal catalysts. This communication presents a highly chemo−and regio-selective tandem Michael sequence, thereby enabling the divergent synthesis of polycyclic γ-lactams. The highly functionalized acyclic precursors constructed via the Ugi four-component reaction, undergo two distinct pathways involving the double Michael reaction. Importantly, the newly synthesized polycyclic spiro-γ-lactams can be readily converted to valuable tetracyclic γ-lactams under mild conditions. Furthermore, all synthesized compounds are evaluated by MTT assay, exhibiting potent anticancer activities. Notably, compound (±) 7h demonstrates displayed the highest cytotoxicity against PANC-1 cell (IC 50 = 90 nM).