Under external-field stimulation, semiconductor activation for catalytic therapy has attracted considerable attention in tumor treatment. However, achieving highly efficient catalytic reactions under limited substrate availability-particularly within the tumor microenvironment-remains the major obstacle limiting the efficacy of catalytic therapies. The construction of heterojunctions effectively suppresses rapid electron-hole recombination, thereby enhancing catalytic efficiency. Nevertheless, maintaining appropriate conduction band (CB) and valence band (VB) positions to preserve strong redox potentials represents a further challenge. To address these limitations, the Z-type heterojunction (Z-HJ) was proposed and has been widely applied in catalytic tumor therapy. This review elucidates the fundamental principles and developmental trajectory of Z-HJs in catalytic tumor therapy, emphasizing their mechanisms for enhancing therapeutic efficacy. It further explores on-demand Z-HJ design strategies that target key pathological features, including cell proliferation, apoptosis, metastasis, and immune suppression. In addition, advancements in AI-driven Z-HJ nanozyme design, theranostic integration, and multimodal synergistic treatment strategies are discussed. Finally, the review summarizes current challenges and outlines future perspectives for Z-HJ-based tumor therapy.