Using various animal models, studies have greatly expanded our understanding of perinatal hypoxia-induced neuronal injury in the newborn at the cellular/molecular levels. However, the synapse-basis pathogenesis and therapeutic strategy for such detrimental alterations in the neonatal brain remain to be addressed. We investigated whether the damaged synaptic efficacy and neurogenesis within hippocampal CA1 region (an essential integration area for mammalian learning and memory) of the neonatal rat brain after perinatal hypoxia were restored by granulocyte-colony stimulating factor (G-CSF) therapy. Ten-day-old (P10) rat pups were subjected to experimentally perinatal hypoxia. G-CSF (10, 30, or 50 μg/kg, single injection/d, P11-16) was s.c. administered to neonatal rats which were analyzed on P17. Perinatal hypoxia reduced the expression in pRaf-pERK1/2-pCREB(Ser-133) signaling, the synaptic complex of postsynaptic density protein-95 (PSD-95) with N-methyl-D-aspartate receptor (NMDAR) subunits (NR1, NR2A, and NR2B), synaptic efficacy, and neurogenesis. A representatively effective dosage of G-CSF (30 μg/kg) alleviated the perinatal hypoxia-induced detrimental changes and improved the performance in long-term cognitive function. In summary, our results suggest a novel concept that synaptic efficacy defects exist in the neonatal brain previously exposed to perinatal hypoxia and that G-CSF could be a clinical potential for the synapse-basis recovery in the perinatal hypoxia suffers.