Purpose – This study aims to explore the potential mechanism of dexmedetomidine in terms of inhibiting inflammation to alleviate early neuronal injury via TLR4/NF-κB pathway in rats with traumatic brain injury. Methods – The model of brain injury was established in rats. After the model was established, the rats were randomly divided into five groups: Sham, Sham + DEX, TBI, TBI + vehicle, and TBI + DEX. Each group included 10 rats. The water content in the brain tissue was measured. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assays were performed on histopathological tissue sections to evaluate neuronal apoptosis. Enzyme-linked immunosorbent assay and PCR were applied to detect the levels of the inflammatory factors, TNF-α, IL-1β, IL-6, and NF-κB. Results – TBI-challenged rats exhibited significant neuronal apoptosis, which was characterized via the wet-to-dry weight ratio, neurobehavioral functions, TUNEL assay results, and the levels of cleaved caspase-3, Bax upregulation, and Bcl-2, which were attenuated by DEX. Western blot, immunohistochemistry, and PCR results revealed that DEX promoted TLR4 expression and upregulated expression of the TLR4 downstream factors, HO-1 and NQO-1. Furthermore, DEX treatment markedly prevented the downregulation of inflammatory response factors, TNF-α, IL-1β and NF-κB, and IL-6. Conclusion – Dexmedetomidine is able to inhibit inflammation and attenuate early neuronal injury in rats with acute brain injury, which may act on TLR4/NF-κB pathway.