Hyperlipidemia is characterized by a high level of blood lipid which poses a serious threat to human health. Coix seed is a traditional crop of medicine and food homology with a wide range of pharmacological actions. To make clear the attenuation effect of coix seed against hyperlipidemia, low and high doses of coix seed extract (CSE) were orally administered to hyperlipidemia model mice developed by high-fat diet (HFD). Our results showed that CSE notably improved liver pathological injury, and oxidative stress, and declined the levels of glucose and lipid in hyperlipidemia mice. Liver metabolomics showed that lipid-related metabolites notably decreased, and pathways of glycolipid metabolism were seriously affected by CSE intervention. Moreover, 16S rRNA sequencing revealed that CSE treatment notably increased the diversity of gut microbiota. Meanwhile, the microbiota with the function of regulating intestinal balance as well as relieving obesity and nervous diseases significantly enhanced while harmful flora notably decreased after CSE intervention. The results of network pharmacology and molecular docking indicated that the PPAR signaling pathway may be the core path of anti-hyperlipidemia for coix seeds. RT-qPCR further verified that the expression levels of genes from the PPAR pathway notably changed by CSE treatment with fat synthesis genes significantly decreased while lipolysis genes notably enhanced. Therefore, coix seed might be a potential candidate for the treatment of hyperlipidemia.