Zinc ions play a vital role in cell metabolism and growth as a common coenzyme factor in many cells. However, when the intracellular Zn²⁺ level exceeds the cell’s tolerance limit, it can cause damage to intracellular mitochondria and induce a burst of reactive oxygen species (ROS), leading to intense intracellular oxidative stress (referred to as “Zn²⁺ interference”). Due to its excellent therapeutic effect and high safety, “Zn²⁺ interference” has emerged as a new strategy for further anti-tumor research. This review aims to summarize the specific applications of zinc-based nanomaterials (such as ZIF-8, ZnO, ZnO₂, ZnS, and Zn-LDH, etc.) that are responsive to tumor microenvironments in different cancer therapies, including chemotherapy, photodynamic therapy, sonodynamic therapy, chemodynamic therapy, piezoelectric therapy, immunotherapy and gas therapy. Moreover, this review analyzes the specific action mechanisms and advantages of different Zn-based nanomaterials in different therapeutic methods. Finally, some recommendations are provided for the design and future utilization of Zn-based nanomaterials in cancer therapy.