AMP-activated protein kinase (AMPK) is a sensor and regulator of cellular energy metabolism potentially Implicated In a broad range of conditions, including obesity and Alzheimer’s disease. Its role in the control of key metabolic enzymes makes this kinase a central player in glucose and lipid homeostasis. Recently, by screening a library of synthetic small molecules selected for their structural similarity with the natural polyphenol resveratrol, we identified RSVA314 and RSVA405 as potent indirect activators of AMPK (half-maximal effective concentration (EC₅₀) = 1 µmol/L in cell-based assays). Here we show that RSVA314 and RSVA405 can significantly activate AMPK and inhibit acetyl-CoA carboxylase (ACC), one target of AMPK and a key regulator of fatty acid biogenesis, in nondifferentiated and proliferating 3T3-L1 adipocytes. We found that RSVA314 and RSVA405 treatments inhibited 3T3-L1 adipocyte differentiation by interfering with mitotic clonal expansion during preadipocyte proliferation (halfmaximal inhibitory concentration (IC₅₀) = 0.5 µmol/L). RSVA314 and RSVA405 prevented the adipogenesis-dependent transcriptional changes of multiple gene products involved in the adipogenic process, including peroxisome proliferator-activated receptor (PPAR)-γ, CCAAT/enhancer-binding protein α (C/EBPα), fatty acid synthase, fatty acid binding protein 4 (aP2), RANTES or resistin. Furthermore, orally administered RSVA405 at 20 and 100 mg/kg/d significantly reduced the body weight gain of mice fed a high-fat diet. This work shows that the novel small-molecule activators of AMPK (RSVA314 and RSVA405) are potent inhibitors of adipogenesis and thus may have therapeutic potential against obesity.