Abstract： Objective To investigate the effects of Edaravone (Ed) on p38mitogen-activated protein kinases/Caspase-3 (p38MAPK/Caspase-3) pathway following the diffuse injury of brain (DIB) in rats, as well as the protective effects of Edaravone on traumatic injury of brain (TIB). Method The TIB models were established by using Marmarou's method in adult male Spraque-Dawlley rats. A total of 250 rats were divided (random number)9nto control group, model group, low-dose Edaravone treatment group and high-dose Edaravone treatment group.The rats were sacrificed separately 1, 6, 24, 48 and 72 hours after DIB and the brain tissues of rats were taken.The morphological changes of neuron in hippocampus region were observed by using Nissl staining. The levels of phosphorylated p38MAPK and Caspase-3 were detected by using immunohistochemistry and Western blot. The learning and memory functions were determined with Morris water maze test from the 3rd to 7th day after injury.Results Compared with control group, some neurons displayed histopathological changes of necrosis and apoptosis in rats of model group. The levels of phosphorylated p38MAPK significantly increased in 1, 6, 24, and 48 hours after injury in rats of model group ( P ＜ 0.05), but there was no statistic significance in increase 72 hours later ( P＞ 0.05). The levels of Caspase-3 significantly increased in 6, 24, 48 and 72 hours after injury in rats of model group ( P ＜ 0.05), but there was no significant difference in increase in one hour after injury (0.59±0.29 vs.0.40±0.17, P ＞0.05).In the Morris water maze test from the 3rd to 6th day, the latency to find the platform significantly prolonged in rats of model group ( P ＜ 0.05), and the numbers of passing the platform by rats decreased on the 7th day (2.28 ± 1.18 vs. 8.20 ± 1.52, P ＜ 0.05). Compared with model group, the levels of phosphorylated p38MAPK in 6, 24 and 48 hours after injury in low-dose Edaravone group were lower (P ＜0.05), but there was no statistical difference in one hour after injury ( P ＞ 0.05). The levels of Caspase-3 in 6,24, 48 and 72 hours after injury in rats of low-dose Edaravone group were lower than those of model group ( P ＜0.05). The latency to find the platform significantly shortened ( P ＜ 0.05) and the numbers of passing the platform by rats increased (4.17 ± 1.15 vs. 2.28 ± 1.18, P ＜ 0.05) in low-dose Edaravone group. The above variables changed more prominently in high-dose Edaravone group. Conclusions Edaravone attenuates p38MAPK pathway activation, lowers the level of Caspase-3 following DIB and protects the rats against the traumatic injury of brain.