Abstract: Most health problems associated with aging, such as wrinkles, heart disease and Alzheimer's disease were caused by excessive oxidative stress in the body. Hyperlipidemia caused by high-fat diet(HFD) would lead to lipid metabolism disorder, oxidative stress and so on. The purpose of this study was to investigate the protective effect of Nostoc sphaeroids Kütz(NSK) on diet-induced hyperlipidemia in mice. In the experiment, six-week-old C57BL/6j male mice were fed with high-fat diet(HFD) for 4 weeks, and then fed with high-fat diet supplemented with different doses of NSK for 6 weeks. Results showed that: High-fat diet could lead to hyperlipidemia and obvious dyslipidemia in mice. The addition of NSK to high-fat diet decreased serum triglyceride(TG), serum total cholesterol(TC), low density lipid cholesterol(LDL-C), while high density lipid cholesterol(HDL-C) increased significantly(P<0.05). It could also significantly reduce the liver index and the enzyme activities of alanine transaminase(ALT) and aspartate transaminase(AST). Through the results of this experiment, it was found that the level of malondialdehyde (MDA) in the liver tissue of 2.5% and 7.5% NSK group decreased, while total antioxidant capacity(T-AOC), hepatic superoxide dismutase(SOD) and glutathione(GSH) increased, and the difference was statistically significant(P<0.05). Furthermore, the expression of LDLR,CYP7a1 and LXR-α in liver tissue of mice supplemented with NSK in HFD significantly increased(P<0.05). In conclusion, NSK hadlipid-lowering effect on HFD-fed mice and it might be related to increase the antioxidant activity and gene expression of LDLR and CYP7a1.