Traumatic brain injury (TBI) leads to acute functional deficit in the brain. Molecular events underlying TBI remain unclear. In mouse brains, we found controlled cortical impact (CCI) injury induced overexpression of the extracellular calcium-sensing receptor (CaSR), which is known to stimulate neuronal activity and accumulation of intracellular Ca2+ and concurrent down-regulation of type B or metabotropic GABA receptor 1 (GABA-B-R1), a prominent inhibitory pathway in the brain. These changes in protein expression preceded and were closely associated with the loss of brain tissue, as indicated by the increased size of cortical cavity at impact sites, and the development of motor deficit, as indicated by the increased frequency of right-biased swing and turn in the CCI mice. Mild hypothermia, an established practice of neuroprotection for brain ischemia, partially but significantly blunted all of the above effects of CCI. Administration of CaSR antagonist NPS89636 mimicked hypothermia to reduce loss of brain tissue and motor functions in the CCI mice. These data together support the concept that CaSR overexpression and overactivity play a causal role in potentiating TBI potentially by stimulating excitatory neuronal responses and by interfering with inhibitory GABA-B-R signaling and that the CaSR could be a novel target for neuroprotection against TBI. © 2013 Mary Ann Liebert, Inc.