Evodiamine (Evo), an alkaloidal component extracted from the fruit of Evodiae fructus (Evodia rutaecarpa Bentham, Rutaceae), decreases the body weight of rats through a poorly defined mechanism. The hypothalamus is one of the areas in the brain linked to the control of food intake and energy expenditure. We postulate that Evo mediates this activity by modulating feeding-related peptides in the hypothalamus. We investigated the effects of Evo on food intake, body weight, the mRNA expression and peptide level of feeding-related peptides in the hypothalamus, in male rats. The juvenile rats of 5 weeks old were used at the start of the experiment. Evo (40 mg/kg or 4 mg/kg) was administered intragastrically for 25 days, and food intake and body weight of rats were recorded daily. Blood samples were collected for leptin radioimmunoassay (RIA). Real-Time PCR was used to analyze the mRNA expression. Western Blotting and immunohistochemistry were used to analyze the peptide. Our results show that intragastric administration of Evo (40 mg/kg) decreased rate of food intake and body weight increase following rat growth, reduced orexigenic neuropeptide Y (NPY) and agouti-gene related protein (AgRP) mRNA levels and NPY peptide level in the arcuate nucleus (ARC) of the hypothalamus, but it increases the circulating level of leptin. Intragastric administration of a smaller dose of Evo (4 mg/kg) was ineffective. These data suggest that Evo decreases food intake, and therefore body weight, partly by down-regulating NPY and AgRP mRNA expression and peptide expression in the ARC of the hypothalamus.