Aim To investigate the effects of fibroblast growth factor-21 （FGF-21） on endoplasmic reticulum stress-induced apoptosis in aorta of ApoE^-/- mice. Methods Twenty-four male ApoE^-/- mice and twelve male C57BL/6J mice were divided into three groups: Control group（n12）, atherosclerosis group （n12） maintained high fat diet with vehicle administration subcutaneously for 4 weeks, and FGF-21 treatment group（n12）: the same fat diet with FGF-21 administration subcutaneously［0.1 mg/（kg·d）］ for 4 weeks. At the end of the study, all mice were sacrificed to detect the plasma FGF-21 levels, histopathological changes and apoptotic rate in aorta, fibroblast growth factor receptor-1 （FGFR-1）, cleaved cysteinyl aspartate specific proteinase-12 （Caspase-12） and C/EBP homologous protein （CHOP） expression of the aortas. Results Compared with control group, atherosclerosis group fed with a high-fat diet showed upregulated levels of FGF-21 in plasma and FGFR-1 protein expression in aorta，and the plaque area, apoptotic rate, cleaved Caspase-12 and CHOP protein expression in aortas were significantly increased （P<0.05）. Compared with atherosclerosis group, FGF-21 group showed less plaque area, apoptotic rate, cleaved Caspase-12 and CHOP protein expression in aortas （P<0.05）. Conclusion FGF-21 can inhibit apoptosis and atherosclerosis possibly by inhibiting expression of pro-apoptotic proteins like cleaved Caspase-12 and CHOP in atherosclerotic aorta of ApoE^-/- mice.