Type 2 diabetes mellitus (T2DM) remains a critical metabolic disorder that demands innovative therapeutic strategies. G protein–coupled receptor 120 (GPR120) has recently emerged as a key regulator of metabolic homeostasis and a promising drug target, yet potent agonists are still limited. In this study, we synthesized 16 flavone and isoflavone derivatives to explore novel GPR120 modulators. Among them, 4′,5,7-trimethoxyflavone (compound 15) showed the strongest activity with an EC₅₀of 0.6μM. In 3T3-L1 adipocytes, compound 15 enhanced glucose uptake through GPR120-dependent AMPK phosphorylation and suppressed lipid accumulation by regulating early adipogenic factors. Zebrafish assays further revealed its ability to modulate pre-insulin marker expression, suggesting systemic metabolic effects. Importantly, compound 15 also acted as a PPARγ antagonist, indicating a dual mechanism in metabolic regulation. These findings highlight compound 15 as a potential lead for the development of dual-acting therapeutics targeting T2DM and metabolic syndrome.