Host defenses in the brain are modulated by the activation of several factors such as oxygen free radical species (ROS), Ca influx, and TRPM2 activation, and they are well-known adverse factors in neurotoxicity and neurodegenerative diseases. Importantly, recent data indicated a protective action of curcumin (CRC) via inhibition of TRPM2 on the inflammation factors, ROS, and apoptosis in hypoxia-induced SH-SY5Y neuronal cells. However, the relationship between interferon gamma (IFNg) exposure and TRPM2 activation in the SH-SY5Y cells are not fully identified. The SH-SY5Y cells as a neuronal cell line model were used in several neuroinflammation studies. Hence, we used the SH-SY5Y cells in the current study, and they were divided into four main groups as control, CRC, IFNg, and IFNg+CRC. The data presented here indicate that IFNg induced excessive Ca influx via activation of TRPM2. The IFNg treatment further increased cell death, cell debris amount, apoptosis, and cytokine generations (IL-1β, IL-6, and TNF-α) which were due to increased cytosolic and mitochondrial ROS generations as well as increased activations of caspase-3 and caspase-9. The expression levels of TRPM2, PARP-1, Bax, caspase-3, and caspase-9 were increased in the cells by the IFNg treatment. However, CRC treatment reduced the increase of expression levels, cytokine generations, caspase activations, ROS release, Ca influx, cell death, and apoptosis levels via inhibition of TRPM2 in the SH-SY5Y cells that were treated with IFNg. Moreover, the treatment of TRPM2 blockers (ACA and 2-APB) potentiated the modulator effects of CRC. In conclusion, these results suggest that neuroinflammation via IFNg lead to the TRPM2 activation in the SH-SY5Y cells, whereas CRC prevents IFNg-mediated TRPM2 activation, cell death, and cytokine generations.