Oleoylethanolamide (OEA) has been previously reported to regulate food intake and body weight gain when administered intraperitoneally. Nevertheless, little information is available with regard to oral administration. To assess whether oral OEA can also exert a similar effect on body fat, we fed C3H mice a high-fat diet supplemented with either 10 or 100 mg/kg body weight OEA for 4 weeks. OEA supplementation significantly lowered food intake over the 4 weeks and decreased adipose tissue mass. Plasma triglyceride levels were also significantly decreased by OEA treatment. In order to identify the potential molecular targets of OEA action, we screened the expression levels of 44 genes related to body fat mass and food intake in peripheral tissues. Adipose tissue fatty acid amide hydrolase (FAAH), intestinal fatty acid transporter/cluster of differentiation 36 and the OEA receptor G-protein-coupled receptor 119 (GPR119) were among the most OEA-responsive genes. They were also associated with reduced body fat pads regardless of the dose. Adipose FAAH was found to be primarily associated with a decrease in food intake. Our data suggest that the anti-obesity activity of OEA partially relies on modulation of the FAAH pathway in adipose tissue. Another mechanism might involve modulation of the newly discovered GPR119 OEA signaling pathway in the proximal intestine. In conclusion, our study indicates that oral administration of OEA can effectively decrease obesity in the mouse model and that modulation of the endocannabinoid fatty acid ethanolamide pathway seems to play an important role both in adipose tissue and in small intestine.