Rare earthelement nanomaterials (REE NPs) hold considerable promise, with high availability and potential applications as superconductors, imaging agents, glass additives, fertilizers additives and feed additives. These results in potential REE NP exposure to humans and the environment through different routes and adverse effects induced by biological application of these materials are becoming an increasing concern. This study investigates the cytotoxicity of REE NPs: nLa2O3, nEu2O3, nDy2O3 and nYb2O3 from 2.5 to 80 μg/mL, in macrophages. A significant difference was observed in the extent of cytotoxicity induced in macrophages by differential REE NPs. The high-atomic number materials (i.e., nYb2O3) tending to be no toxic whereas low-atomic number materials (nLa2O3 and nEu2O3 and nDy2O3) induced 75.1%, 53.6% and 20.7% dead cells. With nLa2O3 as the representative material, we demonstrated that nLa2O3 induced cellular membrane permeabilization, through the sequestration of phosphates from membrane. The further mechanistic investigation established that membrane damage induced intracellular calcium increased to 3.0- to 7.3-fold compared to control cells. This caused the sustained overload of mitochondrial calcium by approximately 2.4-fold, which regulated cell necrosis. In addition, the injury of cellular membrane led to the release of cathepsins into cytosol which also contributed to cell death. This detailed investigation of signaling pathways driving REE NP-induced toxicity to macrophages is essential for better understanding of their potential health risks to humans and the environment.