Obesity remains a major epidemic in developed countries, with a limited range of effective pharmacological treatments. The pharmacological modulation of PPARα, CB1, or GLP-1 receptor activity has demonstrated beneficial effects, including anti-obesity actions. In this study, we evaluated a novel amide derivative of oleic acid and tyrosol (Oleyl hydroxytyrosol ether, OLHHA), a PPARα agonist, and CB1 antagonist, in combination with the GLP-1 agonist liraglutide (LIG), as an effective multitarget therapy to improve both the peripheral and central alterations in an animal model of diet-induced obesity. In rats, exposure to a high-fat high-fructose diet (HFHFD) induced weight gain and increased plasma triglycerides, LDL, and hepatic parameters. In the brain, the HFHFD provoked disruptions in the expression of proteins regulating food intake, the endocannabinoid system, the insulin pathway, and inflammation and resulted in altered tau expression and phosphorylation, thus indicating neurodegenerative changes. Based on our results, the administration of LIG or OLHHA alone was insufficient to completely reverse the alterations noticed at the peripheral and central levels. On the other hand, the combined treatment with both compounds (OLHHA+LIG) was the most effective in promoting body weight loss and ameliorating both the central and peripheral alterations induced by HFHFDs in rats. This multitarget therapeutic approach could represent a promising strategy for treating obesity and associated comorbidities.