Brain injury after focal cerebral ischemia develops from a series of pathological processes, including excitotoxicity, inflammation and apoptosis. However, the results of clinical trials to prevent ischemic brain damage by blocking the detrimental effects are disappointing. Preservation of survival might be also important for treatment of ischemia. Here, we report that proteolytic degradation of the transient receptor potential canonical (TRPC) 6 contributes to ischemic brain damage. The TRPC6 protein level in the neurons was greatly reduced in ischemia. This downregulation was specific for TRPC6 in the members of TRPC subfamily, prior to neuronal death and mediated by the N-methyl-D-aspartate receptor (NMDAR)-dependent calpain proteolysis. A fusion peptide derived from the calpain cleavage site of TRPC6 markedly inhibited calpain-mediated its degradation and protected rat brains from ischemic damage. In transgenic mice overexpressing TRPC6 in the forebrain neurons, the activity of cAMP-response element binding protein (CREB) was enhanced and the infarct volume was greatly reduced. Together, these results suggest that calpain-mediated downregulation of TRPC6 contributes to ischemic cell death and that suppression of its degradation protects neurons from ischemic damage.