With the wide application of nanomaterials in many fields such as food, drug and biomedicine, their negative impacts on the health of human beings in the process of production and uses have attracted much attention. Endoplasmic reticulum (ER), an important organelle and functions in folding and assembling of cellular proteins, synthesis of lipids, and storage of free calcium, is sensitive to stress. ER as one of the most sensitive targets of nanomaterials plays important roles in the toxicity of nanomaterials. This review summarizes the recent studies on the role of ER in the nanotoxicology of several typical nanomaterials, including silver nanoparticles (Ag-NPs), titanium dioxide nanoparticles (TiO2-NPs), zinc oxide nanoparticles (ZnO-NPs), gold nanoparticles (Au-NPs), silica nanoparticles (SiO2-NPs), fullerene, single/multi-walled carbon nanotubes (SWCNTs/MWCNTs) and grapheme/grapheme oxide (GO), and analyzes the difference. The nanomaterials can cause ER stress, and in turn induce apoptosis, inflammation and autophagy. They can also activate the release of Ca2+ from the ER Ca2+ stores through IP3 pathway and further trigger calcium-regulated apoptotic cell death. Nanomaterials tend to accumulate in ER causing damage of ER and inducing ER autophagy.