Multiple‐spiro/fused‐heterocyclic frameworks containing indazolone are structurally unique and represent a class of potentially dominant skeletons. In this work, we successfully fulfilled Rh(III)‐catalyst mediated substrate‐ and pH‐ controlled strategies to construct four novel types of complicated penta‐spiro/fused‐heterocyclic frameworks via C−H activation/[4+1] and [4+2] annulation cascades. This method had mild reaction conditions, a broad scope of substrates, moderate to good yields, and valuable applications, which could realize for the first time the generation of the novel di‐spiro‐heterocyclic and multiple fused‐heterocyclic products with unique structures. More importantly, novel spiro[cyclohexane‐indazolo[1,2‐a]indazole] scaffold constructed by this method exhibited potent antitumor activity against a variety of refractory solid tumors and hematological malignancies in vitro. Overall, our work provided new insights into the construction of complex and diverse multiple spiro/fused‐heterocyclic systems and offered novel valuable lead compounds for the discovery of antitumor drugs. [ABSTRACT FROM AUTHOR]