〔Abstract〕 Objective To investigate the mechanism of propofol alleviating nerve function damage and oxidative stress in rats undergoing cerebral ischemia reperfusion(CI/R) by inhibiting the activation of extracellular signal regulated kinase 1/2(ERK12) and nuclear transcription factor kappa(BNF-κB p65). Methods A total of 75 SD rats were divided into sham operation group, model group, low-dose propofol group, high-dose propofol group and positive control group by random grouping method.The scores of nerve function deficits and postural reflex were compared among all groups. The cerebral infarction rate, cerebral water-containing rate and cerebral index in each group were calculated by 2,3,5-triphenyl tetrazolium chloride(TTC) method. The expression of brain-derived neurotrophic factor(BDNF) and nerve growth factor(NGF) in prefrontal lobe of the rats in each group was detected by RT-PCR and Western blot. The phosphorylation situations of ERK1/2 and NF-κB p65 were detected by Wetern blot. The pathological changes of neurons at hippocampus areas in each group were observed by HE staining. The levels of serum oxidative stress markers [malondialdehyde(MDA), superoxide dismutase(SOD), lactate dehydrogenase(LDH)] were detected by the kits. Results HE staining results showed that the cell distribution was scattered in model group, and there were many necrotic cells. After propofol treatment, the cell distribution in hippocampus areas was relatively even, and necrotic cells were reduced. Compared with sham operation group, scores of nerve function and postural reflex, cerebral infarction rate, cerebral water-containing rate, cerebral index, expression levels of BDNF, NGF, phosphorylated-ERK1/2(p-ERK1/2) and phosphorylated-p65 protein(p-p65), levels of MDA and LDH increased in model group(P<0.05), there was no change in the expression of total ERK1/2 or p65 protein(P>0.05), SOD level decreased(P<0.05). Compared with model group, SOD level increased in low-dose propofol group, high-dose propofol group and positive control group(P<0.05), there was no change in the expression of total ERK1/2 or p65 protein(P>0.05), scores of nerve function and postural reflex, cerebral infarction rate, cerebral water-containing rate, cerebral index, expression levels of BDNF, NGF, p-ERK1/2 and p-p65 protein, MDA and LDH decreased(P<0.05). Conclusion Propofol can protect against cerebral damage caused by ischemia-reperfusion through inhibiting phosphorylation of ERK12 and NF-κB p65 and reducing oxidative stress.