Excess fat accumulation and abnormal metabolism are involved in numerous diseases and thus the research on identification of compounds that can regulate energy homeostasis could significantly facilitate the current effort to prevent and/or treat metabolic disorders. Piceatannol, one of the natural stilbenes, was previously found to decrease lipid accumulation of 3T3-L1 adipocytes. However, its role in fat metabolism in vivo is not known. Thus, Caenorhabditis elegans as an animal model was used in the current study to determine the effect of piceatannol on fat accumulation and its underlying mechanisms. The results showed that 50 and 100 μM piceatannol significantly reduced fat accumulation of wild-type worms grown in normal and high-glucose conditions without altering the growth rate, worm length, pumping rate, or moving speed. The current study further indicated that piceatannol decreased the expression of sbp-1 (encodes an ortholog of mammalian sterol regulatory element-binding protein) and its target gene fasn-1 (encodes an ortholog of fatty acid synthase) as well as increased the expression of hosl-1 (encodes an ortholog of hormone-sensitive lipase) in glucose-treated worms. These data suggested that piceatannol reduced fat accumulation in C. elegans by suppression of genes involved in lipid synthesis and possibly through stimulation of lipolysis. Given that piceatannol exerts similar effects in both C. elegans and 3T3-L1 cells, our finding could provide a mechanistic insight into the role of piceatannol in lipid metabolism in mammals.