Aim To investigate the effect of edaravone dexborneol (ED) on microglial polarization in rats with brain injury caused by hydraulic shock, and explore its mechanism based on Toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) signaling pathway. Methods 32 rats of 205 healthy male SD rats were randomly selected as sham group, the remaining 173 rats were prepared with brain injury model by hydraulic shock method, and 160 model rats were randomly divided into model group, ED (7 mg/kg) group, TAK242 (ressatovir, TLR4 inhibitor, 2 mg/kg) group, ED (7 mg/kg)＋TAK242 (2 mg/kg) group and ED (7 mg/kg)＋lipolyaccharide (LPS, TLR4 agonist, 0.4 mg/kg) group, with 32 rats in each group. After 14 days of continuous intraperitoneal injection once a day, the nerve function, brain water content and blood-brain barrier (BBB) permeability were measured by modified neurological severity score (mNSS), weightlessness method or Evans blue (EB) penetration method, the brain histopathological changes was observed by HE and Nissl staining, the levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), interleukin (IL) 1β, IL-4 and IL-10 in brain tissue were detected by ELISA, the M1 polarization phenotype (CD86/Iba-1) and M2 polarization phenotype (CD206/Iba-1) of microglia cells were detected by immunofluorescence double staining, the mRNA and protein expressions of TLR4, NF-κB p65, NOD-like receptor protein 3 (NLRP3), aquaporin 4 (AQP4) were detected by RT-PCR or Western blot. Results Compared with the model group, the mNSS score, brain water content, BBB permeability of the rats in ED group, TAK242 group, ED＋TAK242 group were significantly were decreased (P＜0.05), the pathological changes such as brain structure disorder, sparse and disordered neuronal arrangement, vacuole-like transformation, inflammatory cell infiltration, decrease in the number of Nishi bodies were significantly improved, the levels of IFN-γ, TNF-α, IL-1β in brain tissue were significantly decreased, while the levels of IL-4, IL-10 were significantly increased (P＜0.05), the mRNA and protein expressions of TLR4, NF-κB p65, NLRP3, AQP4 were significantly decreased (P＜0.05). TAK242 could significantly enhance the regulatory effects of ED on nerve function, brain water content, BBB permeability, inflammatory response, microglia polarization, TLR4/NF-κB signaling pathway related mRNA and protein expression of the rats with hydraulic shock brain injury (P＜0.05), while LPS could significantly reverse the above regulatory effects of ED on the rats with hydraulic shock brain injury (P＜0.05). Conclusion ED may promote the polarization of microglia from M1 phenotype to M2 phenotype by inhibiting TLR4/NF-κB signaling pathway, inhibit inflammatory response and BBB permeability increasing, and thus play a protective role in brain injury caused by hydraulic shock in rats.