Although breast cancer patients respond to the anthracycline doxorubicin, one of the most active chemotherapeutic agents, prognosis remains poor. Recent studies suggested that the lipid-lowering simvastatin holds great promise as cancer therapeutics, which has been shown to inhibit the growth of multiple tumors, including the triple-negative breast cancers. Doxorubicin- and simvastatin-induced cytotoxicity has been associated with the modulation of Ca2+ signaling, but the underlying mechanisms remain incompletely understood. Here, we identify how Ca2+ signaling regulates breast tumor cell response to both drugs. Simvastatin and doxorubicin inhibit human breast cancer cell growth while increase apoptosis in two breast tumor cell lines and in five primary breast tumor specimens through Ca2+ signaling. Signal transduction and proteomic analyses revealed that both simvastatin and doxorubicin trigger persistent cytosolic Ca2+ release, thereby stimulating pro-apoptotic BIM pathway and mitochondrial Ca2+ overload, responsible for its metabolic dysfunction and apoptosis induction. In response to simvastatin and doxorubicin, cytosolic Ca2+ triggers, respectively, Ca2+-independent and -dependent suppression of the ERK1/2 pro-survival pathway. Reduction of the Ca2+ signal by chelation or pharmacological inhibition significantly prevents drugs-mediated anti-cancer signaling pathways. Further study identified that cytoplasmic Ca2+ influxes act upstream of drugs-mediated chemotactic migration, invasion and colony formation inhibition. Furthermore, the in vivo data of the MDA-MB-231 xenograft demonstrated that, by chelating Ca2+-mediated signal, the impact of both drugs on tumor burden inhibition was significantly reduced via caspase-3 deactivation. Our results establish a calcium-based mechanism as a crucial event for execution of the cell-death process triggered by simvastatin and doxorubicin in breast cancer cells.