Dysregulation of energy balance has long been known to play a key role in metabolic diseases, such as obesity, diabetes, and liver diseases among others, and represents an attractive opportunity for therapeutic intervention. Targeting energy intake via injectable incretin analogs has garnered momentous success to address obesity and type 2 diabetes, but are not without shortcomings. Targeting pathways that regulate energy and lipid metabolism represents a promising, complementary approach that can address incretin-class shortcomings such as loss of muscle mass and gastrointestinal complications. Metabolic enzymes and regulators such as acetyl-CoA carboxylase 1 and 2 (ACC1/2) and peroxisome proliferator-activated receptors alpha and delta (PPARa/d) have been shown to significantly impact lipid and energy homeostasis in pre-clinical and clinical studies. We have identified and characterized "RX-01," an orally bioavailable multi-functional small molecule that inhibits ACC1/2 and activates PPARa/d, effectively countering metabolic dysfunction in diet-induced obese mice. We find that RX-01 boosts energy expenditure, and treatment of obese mice with RX-01 resulted in profound beneficial metabolic effects such as marked loss of fat mass while preserving muscle, improved glycemic control, and decreased hepatic steatosis, among others. Additionally, RX-01 effectively reverses hepatic lipid accumulation, inflammation, and fibrosis, key hallmarks of metabolic dysfunction-associated fatty liver disease and steatohepatitis (MAFLD/MASH). RX-01 outperforms clinical pharmaceutical mimics (ACC1/2 inhibitors PPARa/d activators), and synergizes with co-administrated incretin analogs (semaglutide and tirzepatide) in treating obesity and co-morbidities. Together, these data demonstrate that synergistic, specific multi-targeting of lipid and energy homeostasis by RX-01 is an effective approach to address obesity and related metabolic diseases.