Strong P2X7 receptor (P2X7R) activation could cause Ca2+ overload and consequently cell death. We previously showed that Ca2+ store depletion and endoplasmic reticulum (ER) stress were involved in P2X7R-mediated cytotoxicity in differentiated NG108-15 neuronal cells. In this work, we studied whether taurine (2-aminoethanesulfonic acid) could reverse P2X7R-mediated death in differentiated neuronal NG108-15 cells. Taurine (10 mM) could prevent cell death and appearance of cleaved caspase-3 after BzATP (a selective P2X7R agonist) treatment. However, taurine did not protect cells from Ca2+ overload after P2X7R activation. P2X7R-mediated Ca2+ overload by BzATP led to endoplasmic reticulum (ER) Ca2+ depletion and ER stress. We found that although taurine did not prevent Ca2+ store depletion after BzATP stimulation, it prevented appearance of ER stress markers, namely, phosphorylated eukaryotic translation initiation factor 2α (peIF2α) and C/EBP-homologous protein (CHOP). P2X7R activation did not result in mitochondrial Ca2+ ([Ca2+]m) overload, nor did it affect mitochondrial membrane potential. BzATP-induced generation of intracellular reactive oxygen species (ROS) was prevented by taurine. Collectively, neuroprotective effect by taurine may involve suppression of ROS formation and intervention between ER Ca2+ depletion and ER stress.