Traumatic brain injury (TBI) leads to a cascade of neuroinflammation and subsequent long-term cognitive deficits. Alpha melanocyte stimulating hormone (a-MSH) is a neuropeptide that protects against TBI. In this study, we aimed to evaluate the effect of a-MSH on TBI induced brain inflammation. a-MSH improved rotarod latencies during the first 3 days and water maze latencies over 29-32 days. Here, a-MSH-treated mice had significantly lower tumor necrosis factor-alpha (TNF-a) concentrations in the cortex at 30 min and 1 h. The mitogen-activated protein kinase (MAPK) isoforms JNK, ERK, and p38 decreased following administration of a-MSH. The inhibitor of nuclear factor-kB (IkB) kinase (IKK)/Nuclear factor-kB (NFkB) signaling system is a key regulator of inflammation. Phosphorylation of IKK/NFkB increased after TBI but decreased significantly in response to a-MSH. Strongly immunoreactive microglia increased and were observed throughout the hippocampus in the TBI model, whereas a-MSH-treated mice showed less activation. TNF-a concentrations tended to decrease in the hippocampus. These data indicate that a-MSH might attenuate inflammation in a TBI mouse model.