To examine the potential protective impact and underlying mechanism of nerve growth factor on brain tissue in hyperbilirubinemia rats through the downregulation of Fas/Fas ligand expression. Thirty six healthy Sprague-Dawley rats were selected as normal control group, and 0.5 ml saline was injected intraperitoneally. The remaining 24 rats were injected intraperitoneally with 50 μg/g bilirubin to establish the model of hyperbilirubinemia. After the model was established successfully, they were divided into hyperbilirubinemia group and nerve growth factor intervention group. The rats in the nerve growth factor intervention group were intraperitoneally injected with 50 μg/kg/d nerve growth factor once a day for 3 d. Rats in each group were killed and their brain tissues were taken to wait for detection. The changes of pathological morphology and the Fas and Fas ligand were compared between the normal control group at 72 h and the hyperbilirubinemia group at 6 h, 24 h, 72 h and the nerve growth factor intervention group. In hyperbilirubinemia group and nerve growth factor intervention group, the brain tissue of rats had different degrees of neurocyto edema. After 6 h, the brain tissue of both groups had degeneration. After 24 h, the neuron necrosis was obvious. After 72 h, the brain tissue of both groups had glial cell proliferation, nuclear pyknosis and fragmentation. However, the severity of brain tissue in nerve growth factor intervention group was less than that in hyperbilirubinemia group, while that in normal control group was not obvious change. At 6 h, 24 h and 72 h, the Fas in the hyperbilirubinemia group was raised than that of the normal control group; while this in the nerve growth factor intervention group was reduced than that of hyperbilirubinemia. At 6 h, 24 h and 72 h, the Fas ligand in hyperbilirubinemia group was raised than that of normal control group; and it in nerve growth factor intervention group was reduced than that of hyperbilirubinemia group. The expression of Fas/Fas ligand can be downregulated by nerve growth factor, thereby providing protection to the brain tissue of rats with hyperbilirubinemia.