Aim To study the effect of irisin on the process of atherosclerosis in apolipoprotein E knockout (ApoE－/－) mice. Methods ApoE－/－ mice were randomly divided into three groups:normol group, atherosclerosis model group and irisin group, each group contained 10 mice. ApoE－/－ mice in normol group were fed with normal diet and saline, ApoE－/－ mice in atherosclerosis model group were fed with high fat diet and saline, ApoE－/－ mice in irisin group were fed with high fat diet and irisin, all mice were fed for 12 weeks. Total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), the serum levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured by chemical method, HE staining and total oil red O staining were used to analyze the size of aortic atherosclerotic plaque area, the mRNA and protein level of CD36, NF-κB p65, SOD were detected by real-time quantitative PCR (qPCR) and Western blot. Results The area of aortic plaque in atherosclerosis model group was significantly higher than that in normal group, the area of aorta plaque in irisin group was significantly lower than that in atherosclerosis model group. Compared with normal group, body weight of mice, TC, TG, LDLC, MDA, the expression of NF-κB p65 and CD36 mRNA and protein in atherosclerosis model group increased, while the activity of serum SOD and HDLC levels decreased (P＜0.05). Compared with atherosclerosis model group, body weight of mice, TC, TG, LDLC, MDA, the expression of NF-κB p65 and CD36 mRNA and protein in irisin group decreased, while the activity of serum SOD and HDLC levels increased (P＜0.05). Conclusion Irisin can reduce the occurrence and development of atherosclerosis in ApoE－/－ mice, which may be related to its decreasing body weight and blood lipid, inhibition of inflammation and anti-oxidative stress.