Objective <p>Sevoflurane is a commonly applied inhalational general anesthetic, but its related neural injury is unavoidable. This study aimed to investigate the effects of transient receptor potential channel 5 (TRPC5) knockdown on sevoflurane-induced neural injury and its interaction with oxidative stress.</p> Methods <p>HT-22 cells were transfected with siRNA to knockdown TRPC5 and then treated with sevoflurane. Afterward, H₂O₂ treatment was supplemented to induce oxidative stress. After treatment, cell viability, apoptosis rate, reactive oxygen species (ROS), malondialdehyde (MDA), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and p-ERK expression were detected.</p> Results <p>After sevoflurane treatment, apoptosis, ROS, MDA, and LDH increased, whereas cell viability and SOD activity decreased, suggesting that sevoflurane induced neural injury and oxidative stress; moreover, the expressions of TRPC5 and p-ERK increased after sevoflurane treatment. TRPC5 knockdown increased cell viability and the levels of ROS, MDA, and LDH, suggesting that it relieved sevoflurane-induced neural injury and oxidative stress. Afterward, H₂O₂ intervention decreased cell viability and SOD activity, but exacerbated apoptosis as well as levels of ROS, MDA, and LDH in cells under sevoflurane treatment; importantly, H₂O₂ intervention attenuated the effects of TRPC5 knockdown on the above six indices, indicating that oxidative stress might mediate the effects of TRPC5 knockdown on sevoflurane-induced neural injury. Moreover, TRPC5 knockdown downregulated the p-ERK expression, while H₂O₂ intervention upregulated it, in cells under sevoflurane treatment.</p> Conclusion <p>TRPC5 knockdown may relieve sevoflurane-induced neural injury by suppressing oxidative stress, supporting its potential as a target for sevoflurane-induced neural injury, but further validation is still needed.</p>