We tested the effects of Oenanthe javanica (OJ) on hepatic fat accumulation and plasma biochemical profiles in a nonalcoholic fatty liver disease model (NAFLD). Rats were divided 5 groups and fed the following diets for 6 weeks: normal rat chow diet (CHOW), high-fat high-cholesterol diet (HFCD), HFCD with the water extract of OJ (HFCD+W), HFCD with the n-butanol extract of OJ (HFCD+B), and HFCD with metadoxine (HFCD+M). Metadoxine (pyridoxine-pyrrolidone-carboxylate) is being used to treat alcoholic fatty liver and has been suggested that it can be effective for treating NAFLD. The HFCD gained significantly more body weight and visceral fat mass and had significantly higher levels of plasma glucose, triglyceride, cholesterol, and liver triglyceride content than the CHOW. The water- and n-butanol extracts of OJ improved the elevated plasma triglyceride and glucose levels induced by high-fat high-cholesterol diet and lowered triglyceride content in the liver. Similarly, the treatment with metadoxine reversed the increased plasma glucose and triglyceride and showed a tendency to decrease hepatic fat accumulation. However, these supplements did not change body weight or visceral fat mass. These results indicate that OJ extracts improve changes in hepatic fat accumulation, plasma glucose, and lipid profiles induced by high-fat high-cholesterol diet but did not affect visceral obesity. In conclusion, the water- and n-butanol extracts of OJ and metadoxine improved hepatic fat accumulation, hyperglycemia, and dyslipidemia induced by high-fat high-cholesterol diet although the effect of metadoxine on fatty liver was not significant, suggesting their potential use for the prevention and treatment of NAFLD.