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Brazilein has been shown to exert an immune regulation effect on regeneration in the central nervous system, but there is currently no consensus regarding its effect on sciatic nerve injury. In the current study, western blot and real-time PCR detection revealed that, after 16 and 8 g/kg of brazilein intervention, the amount of S100 protein and mRNA at L4-6 spinal segments of sciatic nerve injured mice was significantly greater than after 4 g/kg brazilein administration, and in an untreated model group. Luxol Fast Blue myelin staining revealed that neural regeneration after 16 and 8 g/kg of brazilein intervention was significantly better than after 4 g/kg brazilein administration, and in the model group. In addition, electrophysiological and immunohistochemical examinations further confirmed the effect of brazilein in repairing sciatic nerve injury in BALB/c mice. These results indicated that brazilein was able to activate the S100 in anterior horn cells of the spinal cord, promoting sciatic nerve regeneration and repair. Both moderate and high doses were found to exert significant effects.