Low levels of oxygen have harmful effects on cells especially in neurons because of their vulnerable status for oxygen consumption. Intracellular calcium concentration ([Ca2+]i) is accumulated by several kinds of calcium-permeable channels including the Transient Receptor Potential (TRP) channels. The TRPM7 cation channels are calcium ion (Ca2+) permeable non-selective cation channels belonging to TRP superfamily. The TRPM7 is expressed in different organs of the human body including nervous system components especially in the brain. Some of the TRP channel subtypes are related to oxidative stress and increased oxidative stress triggers channel activity. Recently, TRPM7 cation channels involved in hypoxia. Hence, alterations of [Ca2+]i may be a key factor inTRPM7activity in hypoxia and preventing hypoxic injury of neurons TRPM7 could be a therapeutic target. Therefore, it has been investigated effects of downregulation of TRPM7 cation channels by siRNA applications to induce getting TRPM7 activity down. The role of silencing of TRPM7 cation channels on apoptosis and cell morphology, production of intracellular reactive oxygen species (iROS), mitochondrial membrane depolarization (MMD) levels, enzymatic activity values of caspase 3, 8 and 9 in SH-SY5Y neuronal cells investigated in this study. It has been shown that the downregulation of TRPM7 cation channels may prevent cell death and protect cellular morphology and viability in neuronal cells after chemical hypoxia induction. Decreasing TRPM7 channel activity may also decrease calcium overload and it is a key regulatory function of TRPM7 channels in hypoxic conditions. In conclusion, TRPM7 cation channel antagonists or suppression of the channel expression by genetic manipulations can be a useful and potential therapeutic approach against neuronal hypoxia-related cell death.