Curcumin, the primary bioactive substance in turmeric, is known to be associated with weight loss. In this study, we employed Caenorhabditis elegans, a well-established in vivo nematode model to explore the role of curcumin in regulating lipid metabolism. C. elegans administrated with curcumin (10, 25 and 50 μM) exhibited significantly reduced fat accumulation, along with smaller body size (width) when compared to the control, without significantly affecting the feeding behavior. Locomotive activity (average moving speed) was significantly increased by curcumin treatment, suggesting a potential increase in energy expenditure. The reduced fat accumulation by curcumin was dependent on lipogenesis-associated genes, sbp-1 (encodes the homolog of sterol response element binding proteins) and fat-6 (encodes a homolog of stearoyl-CoA desaturase), as curcumin significantly down-regulated the expression levels of these two genes and its fat reduction effect was nulled by the mutation of sbp-1 and fat-6. Additionally, the increased locomotive activity by curcumin was dependent on sbp-1. Current results suggest that curcumin decreases fat accumulation by inhibiting sbp-1/fat-6-mediated signaling in Caenorhabditis elegans.