Objective To investigate the protective effect of dexmedetomidine to regulate TLR4 expression on oxygen glucose deprivation injury in neurons and its mechanism. Methods PC12 cells were cultured in vitro, and the oxygen glucose deprivation cell model was generated. The cell survival rate was detected by CCK-8 test, the expressions of Bax, Bcl-2 and TLR4 proteins were detected by Western blot, the expression of TLR4 mRNA was detected by RT-PCR,and the levels of TNF-α and IL-6 were detected by ELISA after treatment with low (0. 1 μmol/ L), medium (1. 0 μmol/ L)and high doses (10. 0 μmol/ L) of dexmedetomidine for 24 h. In the replicating oxygen-deprived cell model, the expression of TLR4 was inhibited by the TLR4 inhibitor TAK-242. Dexmedetomidine altered the cell survival rate, and levels of Bax,Bcl-2, TLR4, TNF-α and IL-6 proteins. Results The survival rate of PC12 cells was increased, the expressions of Bax,TLR4, TNF-α, and IL-6 proteins, and TLR4 mRNA were decreased, and the expression of Bcl-2 protein was increased ( P <0. 05). This was concentration-dependent after treatment with low, moderate, and high dose dexmedetomidine. After TAK-242 treatment, the expression of TLR4 was decreased, the survival rate of PC12 cells was increased, the expressions of Bax, TNF-α, and IL-6 proteins were decreased, while the expression of Bcl-2 protein was increased ( P <0. 05). The effect of TAK-242 was enhanced after treatment with dexmedetomidine ( P < 0. 05). Conclusions Dexmedetomidine protected neurons from oxygen glucose deprivation by inhibiting the expression of TLR4.