Mitochondria, as the "the power plants" of cells, have been extensively studied because of their biological functions of providing energy and participating in signaling pathways. In parallel, calcium (Ca2+) plays a vital role in the homeostasis balance and function coordination of mitochondria, especially in cancer cells which metabolize frequently to maintain their growth. On this basis, Ca2+ overload has been an efficient, yet safe theranostic model for cancer therapy, by activating mitochondrial apoptosis pathways to achieve cancer suppression. However, the integration of functional units mediating Ca2+ overload into the nanoplatform remains a difficult but significant task. This review aims to highlight meaningful designs of nanoplatforms for Ca2+ overload, including monotherapy and combination therapy. In addition, perspectives on further development of Ca2+ overload are provided, mainly emphasizing scientific restrictions and future exploitation directions.