Apoptosis/cell death and reactive oxygen species (ROS) via overload free Ca2+ and Zn2+ uptake into mitochondria are emerging as crucial events in the etiology of hypoxia (HPX)-induced neurodegenerative diseases. The neuroprotective actions of curcumin (CURC) via modulation of oxidative stress and the PARP1-dependent activated TRPM2 cation channel on the ROS generation and cell death in several neurons have been recognized. However, the molecular mechanisms underlying CURC's neuroprotection remain elusive. We investigated the role of CURC via modulation of TRPM2 on cell death and oxidative cytotoxicity in SH-SY5Y neuronal cells. The SH-SY5Y cells were divided into five groups as follows: CURC (10 mu M for 24 h), HPX (200 mu M CoCl2 for 24 h), CURC + HPX, and HPX + TRPM2 blockers (2-APB-100 mu M or ACA-25 mu M for 30 min). In some experiments, the cells in the HPX groups were additionally incubated with PARP1 (PJ34) and Zn2+ (TPEN) inhibitors. The exposure of CoCl2 induced increases of TRPM2 current density and Ca2+ fluorescence intensity with an increase of mitochondrial membrane depolarization and ROS generation. When HPX-induced TRPM2 activity was blocked by 2-APB and ACA, or the cells were treated with CURC, the increase of ROS generation, the expression levels of TRPM2 and PARP1 were restored. The levels of apoptosis and cell death in the cells were enriched with increases of caspase-3 and -9 activations, although they were decreased by CURC treatment. HPX-induced increase of cytosolic Zn2+ was attenuated by the TPEN and CURC treatments. In conclusion, CURC attenuates HPX-induced mitochondrial ROS generation, apoptosis, cell death, and TRPM2-mediated Ca2+ signaling and may provide an avenue for treating HPX-induced neurological diseases associated with the ROS, Ca2+, and Zn2+.