Conditions associated with low serum magnesium in humans (hypomagnesemia) can lead to seizures. The channel kinase TRPM7 is the most prominent protein in mammals that regulates cellular and systemic magnesium levels. The present study demonstrates for the first time that TRPM7 activity contributes to seizure-like brain activity in rodents. The inhibition of TRPM7 by the specific inhibitor waixenicin A and the more promiscuous inhibitor carvacrol completely abolishes epileptiform seizure activity in rodent hippocampal brain slices. This holds true whether seizure activity was induced by hypomagnesemia or by inhibition of GABA(A) receptors. These findings provide a new pathway to control seizures through therapeutically targeting TRPM7. At the same time, they highlight the importance of maintaining adequate magnesium levels for functional brain activity.