Granulocyte colony-stimulating factor is an activator of bone marrow stem cells and is currently mainly used to prevent and treat leukopenia caused by radiotherapy or chemotherapy of tumors. Now there is increasing evidence that granulocyte colony-stimulating factors exert important neuroprotective functions to the central nervous system through a variety of signaling pathways. In animal experiments, granulocyte colony-stimulating factor has been shown to play a protective role in neonatal hypoxic-ischemic encephalopathy by anti-apoptotic effect, anti-inflammatory effect, stabilizing blood-brain barrier, inhibiting hypothalamic-pituitary-adrenal axis activity, promoting neurovascular regeneration and mobilizing hematopoietic stem cells. This paper reviews the signaling pathway and brain protective mechanism of granulocyte colony stimulating factor in the treatment of neonatal hypoxic-ischemic encephalopathy, and the methods of granulocyte-colony stimulating factor combined with other drugs in the treatment of neonatal hypoxic-ischemic encephalopathy.