Objective To investigate the effect and mechanism of mannose exposure on the hyperlipidemia in apolipoprotein (Apo)E-deficient mice. Methods Ten ApoE-deficient mice (6 weeks old, male) were divided into control group and mannose group (5 in each group). A hyperlipidemia model was established using high fat and high cholesterol purified feed. The mice in the control group were fed with drinking water, while the mice in the mannose group were fed with drinking water containing 2% mannose (w/v). Plasma total cholesterol and triglyceride concentrations were measured using their respective kits. Plasma lipoproteins were separated by fast protein liquid chromatography, and the Apo and cholesterol levels were measured. The mRNA and protein expression levels of lipoprotein metabolism-related genes in the liver and jejunum were detected by quantitative polymerase chain reaction and Western blotting, respectively. Results Compared with the control group, the levels of plasma triglyceride and total cholesterol of mice in the mannose group were significantly increased (P＜0.05, P＜0.01), accompanied by significantly higher levels of cholesterol and ApoB100 protein in very low-density lipoprotein and lower levels of ApoA1 and ApoA4 in high-density lipoprotein. The expression of ApoA1 protein in the liver and jejunum of mice in the mannose group was downregulated compared to the control group, while the downregulation of ApoA4 protein expression was only observed in the jejunum. Conclusion Mannose exposure affects lipoprotein metabolism and aggravates the hyperlipidemia in ApoE-deficient mice.