Some polyphenols derived from plants may ameliorate hyperlipidemic fatty livers; therefore, we hypothesized that polyphenol-rich Chrysanthemum morifolium extract (CME) may exert an inhibitory effect on the formation of hyperlipidemic fatty livers in mice. This study aimed to examine the effects of CME on lipids in blood and liver and on peroxisome proliferator-activated receptor (PPAR)α-mediated gene expression. Mice with hyperlipidemic fatty livers induced by orally administering high-fat milk via gavage and being simultaneously treated with 75 to 300 mg/kg CME for 6 weeks. After CME addition, the serum total cholesterol levels and hepatic weight coefficients decreased, but no significant reduction in the serum triacylglycerol levels were observed. It is important to note that CME might decrease hepatic lipid accumulation, sterol regulatory element binding protein-1c, and fatty acid synthase expression and increase hepatic PPARα, lipoprotein lipase, and cholesterol 7α-hydroxylase expression. However, the expected reduction in hepatic diacylglycerol acyltransferase mRNA expression was not observed. These findings demonstrate that polyphenol-rich CME may prevent hyperlipidemic fatty liver in mice, and its mechanisms may be related to the modulation of sterol regulatory element binding protein-1c, FAS, lipoprotein lipase, and cholesterol 7α-hydroxylase 1 expression through the PPARα-mediated pathway.