Hydrogen sulfide (H2S) is a lipid-soluble, endogenously produced gaseous messenger molecule collectively known as gasotransmitter. Over the last several decades, gasotransmitters have emerged as potent cytoprotective mediators in various models of tissue and cellular injury. In this study, we performed a weight-drop traumatic brain injury (TBI) model in adult mice and investigated changes of H2S and its possible role in the pathogenesis after TBI. Expression of Cystathionine-β-synthase (CBS) mRNA as H2S-producing enzymes in mouse brain was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). From the results of RT-PCR, it was found that the expression of CBS was down-regulated in mouse brain cortex and hippocampus after brain injury. Western blot analysis revealed that CBS was present in normal mouse brain cortex and the hippocampus. It gradually decreased, reached its lowest level and then increased. Hydrogen sulfide in the cortex and hippocampus exhibited dynamic changes after brain injury, in parallel with CBS mRNA and protein expression. Moreover, pretreatment with the H2S donor (NaHS) could protect the neuron against the injury induced by TBI. Noticeably, the H2S donor NaHS could reduce TBI-induced injury assessed with lesion volume. These data suggested that H2S may have a therapeutic potential against neuron damage.