Our work was attempted to evaluate the effect of dioscin on brain injury following traumatic brain injury (TBI) and explore its mechanism. Methods: TBI model was constructed in C57BL/6 mice by Feeney’s free-falling method in vivo and in primary cortical neurons by wound scratch assay in vitro. Then, TBI model was treated with dioscin in vivo and in vitro. Cerebral edema and Neurologic severity score (NSS) were evaluated in mice 24 h post TBI construction. The nerve cell injury was assessed by Nissl staining, and the microglia activation and phenotypic transformation were analyzed by immunofluorescence staining. The expression levels of proinflammatory factors (IL-1β, IL-6 and TNF-α) were measured by RT-qPCR assay and MAPK pathway related proteins (p-ERK1/2, p-P38 and p-JNK) were observed by western blot. Results: Dioscin significantly attenuated TBI induced cerebral edema, neurological dysfunctions and microglia mediated inflammation, reflected by reduced brain water content, NSS score, M1 microglia percentage and proinflammatory factors expression (all P<0.05). The levels of phosphorylated ERK1/2, P38 and JNK were obviously declined in TBI mice after treated with dioscin (P<0.05). Conclusion: Dioscin elicited neuroprotective effect against TBI induced injury through MAPK pathway.