Traumatic brain injury causes axon tearing and synapse degeneration resulting in multiple neurological dysfunctions and early neurodegenerations; the repair of axonal and synapse structures is critical in maintaining neuronal function. C-C Motif Chemokine Ligand 5 (CCL5) shows neuroprotective function by promoting neurite outgrowth and synaptogenesis. This study used a weight-drop model to induce mild brain trauma in both C57BL/6 (wildtype, WT) and CCL5 knockout (CCL5-KO) mice. The recovery of motor and sensory neurological functions, and synapse structure and proteins were impaired in CCL5-KO mice; administrated recombinant CCL5 (300 pg/g once, and 30 pg/g every two day for one month) through nasal delivery improved those neurological dysfunctions. Using LC-MS/MS analysis, we identified that CCL5 affected the expression of “Nervous system development and function” related proteins including axongenesis, synaptogenesis, neuron development and myelination signaling pathways following injury. CCL5 activated PI3K/mTOR signaling to promote axon and synapse regrowth; study also identified that CCL5 contributed to Neuregulin/ErbB/Erk and FGF/FAK signaling pathway activation and facilitated oligodendrocyte remyelination in cortical tissue after trauma. Activating a co-receptor -CXCR4 promoted neuronal migration and reformation. Thus, CCL5 is essential in intrinsic regeneration system activation including axon and synapse regrowth, remyelination and proper wiring of cortical circuits after brain injury.