Despite the health benefits of Vitis vinifera L. leaves, its anti-obesity potential has not been fully explored. In this work, we showed that Vitis vinifera L. leaf extract (VLE) inhibits the pancreatic lipase activity. Intragastric administration of VLE to mice led to a significant decrease in the body weight, tissue fat accumulation, levels of cholesterol, low-density lipoprotein and triglyceride compared to mice fed with high fat diet. We also found a lower level of neuropeptide-Y (NPY) in the serum and hypothalamus and a higher level of fibroblast growth factor 15 in mice supplemented with VLE. These results suggested that VLE regulates both the NPY-mediated pathway and the bile acid-FGF15 pathway to control energy metabolism and body weight gain. The composition of VLE was further investigated by a targeted metabolomics approach, which identified 21 compounds including phenolic acids, flavones, flavanols, flavanones, coumarins, and stilbenes. Taken together, we demonstrated the capacity of grape leaves in reducing obesity, which could be mediated by NPY and bile acids. Identification of putative active compounds in VLE also open the path for further studies to determine their effectiveness individually to treat obesity.