Objective To investigate the cerebral protective effect of cinnamaldehyde (CA) in mice with focal cerebral ischemia and related mechanism.Methods Male CD-1 mice were treated with intraperitoneal injection of CA, and the modified suture method was used to establish a mouse model of permanent right middle cerebral artery occlusion (MCAO). Healthy adult male CD-1 mice were randomly divided into MCAO group and low-, middle-, and high-dose CA groups (CA25, CA50, and CA 75 groups treated with intraperitoneal injection of CA at concentrations of 25, 50, and 75 mg, respectively, in addition to the treatment in the MCAO group). At 24 hours after surgery, neurologic impairment score, cerebral infarct volume, and brain water content were measured to evaluate the cerebral protective effect of CA. Western blot and quantitative real-time PCR were used to measure the expression of Toll-like receptor 6 (TLR6), tumor necrosis factor receptor-associated factor 6 (TRAF6), and nuclear factor-kappa B (NF-κB) in brain tissue.Results Compared with the MCAO group, the CA50 group had a significant improvement in median neurological score (2.0 vs 3.5, P<0.05) and significant reductions in brain water content (83.72%±0.73% vs 85.09%±0.95%, P<0.05) and cerebral infarct volume (0.45±0.06 vs 0.54±0.02, P<0.05). Compared with the MCAO group, the CA50 group had significant reductions in the mRNA expression of TLR6, TRAF6, and NF-κB (TLR6:3.26±0.03 vs 6.32±0.07, P<0.05; TRAF6:1.88±0.21 vs 3.33±0.48, P<0.05; NF-κB:1.47±0.33 vs 4.21±0.57, P<0.05), as well as significant reductions in the protein expression of TLR6, TRAF6, and nuclear NF-κB (TLR6:0.12±0.01 vs 0.19±0.03, P<0.05; TRAF6:0.45±0.09 vs 0.67±0.07, P<0.05; NF-κB:0.32±0.06 vs 0.46±0.06, P<0.05).Conclusions CA exerts a cerebral protective effect in mice with focal cerebral ischemia, possibly by inhibiting the TLR6/TRAF6/NF-κB signaling pathway.