Hypoxic-ischemic encephalopathy (HIE) is a serious clinical problem, responsible for many cases of motor impairment, cognitive deficits, and mortality. Transient receptor potential canonical (TRPC) channels are nonselective cation channels that play a role in many disorders, including trauma, pulmonary hypertension, and excitotoxicity. However, the properties and underlying mechanisms of TRPC channels in HIE are still controversial. Extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin (mTOR) are central signaling pathways that transmit signals from extracellular to intracellular agents and mediate prosurvival, proliferation, and motility proteins. The relationship between TRPC channels, ERK, and mTOR is unclear. We used oxygen-glucose deprivation/reoxygenation in primary cortical neurons and PC12 cells to mimic an HIE episode. The potential effects and mechanisms of TRPC channels were examined. MNC (M: MK-801; N: nimodipine; C: CNQX) were used to exclude the interference of N-methyl-D-aspartate receptors, AMPK receptors, and calcium channels. We administered TRPC inhibitor SKF96365 to the cells, and then measured cell apoptosis and expression of ERK and mTOR signal pathways. At the same time, an ERK inhibitor or an mTOR agonist was used to further ensure the relation between TRPC channels and ERK, mTOR. Results showed that hypoxia-ischemia clearly induced cell apoptosis, activated the ERK pathway, and suppressed the mTOR pathway. Blocking of TRPC channels could enhance hypoxia-ischemia-induced apoptosis and lead to increased p-ERK pathway activity and decreased p-mTOR pathway activity. However, the ERK inhibitor or the mTOR agonist could reverse the effect of SKF96365. This study suggests that TRPC channels may be an effective treatment for HIE, regulating the ERK and mTOR pathways.