Sinomenine (SINO), which is used clinically to treat rheumatoid arthritis and neuralgia, is derived from the root and stems of . SINO has been reported to exert analgesic, sedative and anti-inflammatory effects, and provides a protective role against shock and organ damage. Studies have suggested that SINO primarily exerts it anti-inflammatory function by inhibiting NF-κB signaling. There is also evidence to indicate that SINO may regulate inflammation Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling. The present study aimed to investigate whether the anti-inflammatory and cerebral protective effects of SINO were induced through Nrf2 both and . The results revealed that SINO significantly upregulated Nrf2 protein expression levels, increased Nrf2 nuclear translocation and the upregulated the protein expression levels of downstream factors. The treatment of a middle cerebral artery occlusion model mice with SINO effectively reduced cerebral damage and inflammation, and restored the balance in cerebral oxidative stress. In addition, SINO treatment also promoted Nrf2-dependent microglia M1/M2 polarization and inhibited the phosphorylation of IκBα as well as NF-κB nuclear translocation. This revealed an important upstream event that contributed to its anti-inflammatory and cerebral tissue protective effects. In conclusion, the findings of the present study identified a novel pathway through which SINO may exert its anti-inflammatory and cerebral protective functions, and provided a molecular basis for the potential applications of SINO in the treatment of cerebral inflammatory disorders.