Increasing evidence has confirmed that whole grain oats are effective in regulating hyperlipidemia. However, which specific ingredient is crucial remains unclear. This study focused on which whole grain components, oat phenolic compounds (OPC) or oat β-glucan (OBG), can regulate lipid metabolism and gut microbiota. The experiment unveiled that OPC and/or OBG not only reduced the body weight and fasting blood glucose (FBG) but also regulated serum and hepatic lipid levels in high-fat-diet (HFD) fed mice. There was no significant difference in the regulatory effects of OPC and OBG (p > 0.05). The combination of OPC and OBG (OPC + OBG) significantly decreased the body weight (p < 0.01) and reduced the blood glucose (p < 0.01) and lipid profile levels (p < 0.01). The real-time quantitative PCR (RT-qPCR) study revealed that OPC + OBG significantly altered mRNA expression related to lipid metabolism. Histopathological analysis showed that OPC + OBG improved liver lipid deposition as well as liver oxidative stress (p < 0.05). In addition, OPC + OBG combination regulated the gut microbiota community phenotype and increased probiotics. OPC + OBG significantly increased the abundance of Bacteroidetes and reduced the abundance of Firmicutes (p < 0.05) compared with the OPC and OBG fed mice. In conclusion, OPC + OBG has a synergistic effect in alleviating hyperlipidemia via lipid metabolism and gut microbiota composition. This finding also provided a potential justification for the advantages of whole grains in preventing hyperlipidemia.