Globally and within Egypt, obesity fuels a growing health crisis, demanding novel therapeutic approaches rooted in systems medicine. This framework promotes the classification of diseases based on causal molecular mechanisms and use multi-target interventions to achieve synergistic effects within these pathways. Our previous research identified a dysregulated interaction among fatty acid synthase (FASN), arginase (ARG), and endothelial nitric oxide synthase (eNOS) as a potential mechanistic driver of obesity and its sequelae. To address this, we designed a targeted therapeutic approach targeting malfunctioning at this dysfunctional FASN/ARG/eNOS network to enhance outcomes in obesity-related cardiovascular complications. We induced obesity in rats using a high-fructose, high-salt diet for 10 weeks, then randomized them into six groups: control, obese, and four obese treatment arms receiving orlistat (FASN inhibitor), norvaline (ARG inhibitor), citrulline/folic acid (eNOS recoupling), or their combination for 5 weeks. Although individual treatments offered benefits – orlistat reducing adiposity and improving some metabolic and cardiac markers, norvaline improving blood pressure (BP) and glycemic control, and citrulline/folic acid enhancing antioxidant defense and vascular function – the combined intervention yielded a striking synergistic effect. This multi-pronged approach most effectively reduced adiposity, normalized key metabolic parameters, conferred robust protection against cardiac remodeling (both structural and functional), significantly improved BP regulation, and modulated cardiac oxidative stress and inflammation. Our findings strongly indicate that simultaneously targeting the FASN/ARG/eNOS axis with mechanism-based therapies represents a novel and highly promising approach to comprehensively mitigate obesity and its devastating cardiovascular consequences.