Obesity, a global health crisis associated with diabetes, cardiovascular diseases, and cancer, has spurred interest in plant-derived bioactive compounds like polyphenols and flavonoids for their lipid-modulating potential. This study employed Caenorhabditis elegans—a genetically tractable model with conserved metabolic pathways—to investigate the anti-obesity effects of three compounds: hexahydrocurcumin (HHC)， esculetin and Nordihydroguaiaretic acid (NDGA). HHC, a stable curcumin derivative, reduced C. elegans triglyceride levels by 13% at 50 μM without altering feeding behavior or physiology. Genetic analyses revealed its dependence on nhr-49, tub-1, aak-1/aak-2, and fat-7, suggesting multi-pathway regulation of fat storage. Esculetin, a coumarin from plants like chicory and cranberries, decreased fat content (8% at 100 μM; 14% at 200 μM) while maintaining normal food intake. Its effects were abolished in mutants of aak-2, implicating AMPK pathway may be evolved. NDGA, a natural lipoxygenase inhibitor from the creosote bush, reduced fat accumulation in C. elegans by 13% at 50 μM and 39% at 100 μM and suppressed food intake. Its effects were abolished in daf-16 and fat-6 mutants, and it promoted DAF-16 nuclear translocation, suggesting a gene-targeted anti-obesity mechanism. These findings highlight conserved pathways through which plant bioactive compounds modulate obesity-related processes. The study underscores C. elegans as a robust platform for screening anti-obesity compounds and elucidating their genetic targets.