Neuro-inflammation and activated microglia play important roles in neuron damage in the traumatic brain injury (TBI). In this study, we determined the effect of neural network reconstruction after human umbilical cord mesenchymal stem cells (UMSCs) combined with monosialotetrahexosy 1 ganglioside (GM1) transplantation and the effect on the neuro-inflammation and polarization of microglia in a rat model of TBI, which was established in male rats using a fluid percussion brain injury device. Rats survived until day 7 after TBI were randomly treated with normal control (NC), saline (NS), GM1, UMSCs, and GM1 plus UMSCs. Modified neurological severity score (mNSS) was assessed on days 7 and 14, and the brain tissue of the injured region was collected. Immunofluorescence, RT-PCR, and western blot analysis found that inhibitory neuro-inflammatory cytokines TGF-β and CD163 protein expression levels in injured brain tissues were significantly increased in rats treated with GM1 + UMSCs, GM1, or UMSCs and were up-regulated compared to saline-treated rats. Neuro-inflammatory cytokines IL-6, COX-2 and iNOS protein expressions were down-regulated compared to rats treated with saline. The protein expression levels of NE, NF-200, MAP-2 and β-tubulin III were increased in the injured brain tissues from rats treated with GM1 + UMSCs, or GM1 and UMSCs alone compared to those in the rats treated with NS. The protein expression levels in rats treated with GM1 plus UMSCs were most significant on day 7 following UMSC transplantation. The rats treated with GM1 plus UMSCs had the lowest mNSS compared with that in the other groups. These data suggest that UMSCs and GM1 promote neural network reconstruction and reduce the neuro-inflammation and neurodegeneration through coordinating injury local immune inflammatory microenvironment to promote the recovery of neurological functions in the TBI.