Objectives : In this study, we investigated the effect and the underlying mechanism of ethanol extract of Benincasa seeds on a cellular model of non-alcoholic fatty liver disease (NAFLD) established by treating HepG2 cells with palmitate. Methods : We evaluated ethanol extract of Benincasa seeds (EEBS) for its hepatic lipid-lowering potential in fatty acid overloaded HepG2 cells. After incubation in palmitate containing media with or without EEBS, intracellular neutral lipid accumulations were quantified by Nile red staining. We also investigated the effect of EEBS on lipogenesis and ${eta}$-oxidation. $LXR{alpha}$-dependent SREBP-1c activation, expression of lipogenic genes, and expression of ${eta}$-oxidation related genes were determined with or without pretreatment of EEBS. Results : EEBS significantly attenuated palmitate-induced intracellular neutral lipid accumulation in HepG2 cells. EEBS suppressed fatty acid synthesis by inhibiting $LXR{alpha}$-dependent SREBP-1c activation. EEBS also repressed SREBP-1c mediated induction of lipogenic genes, including ACC, FAS, and SCD-1. However, EEBS had no effect on ${eta}$-oxidation related CPT-1 and $PPAR{alpha}$ gene expression. Conclusions : Our results suggest that EEBS has an efficacy to decrease hepatic lipid accumulation, and this effect was mediated by inhibiting the $LXR{alpha}$-SREBP-1c pathway that leads to expression of lipogenic genes and hepatic steatosis. Therefore, the Benincasa seeds may have a potential clinical application for treatment of this chronic liver disease.