Introduction: Obesity is one of the major risk factors for many diseases such as cardiovascular disease and diabetes. Although a few studies have been shown the pharmacological properties of Peganum harmala, there is no data on the anti-obesity effect of this plant. This study was designed to investigate the effect of the hydroalcoholic extract of Peganum harmala seed on the weight and blood biochemical parameters in male wistar rats. Materials and Methods: Fifty male Wistar rats were categorized into 5 groups: Negative control group (standard diet) positive control group (high-fat diet with 4% of fat) treatment groups (high-fat diet + hydroalcoholic extract of Peganum harmala at 200 and 400 mg/kg/day and high-fat diet + Orlistat at 200 mg/kg/day). Extracts and orlistat were administrated by gavage for 8 weeks, and levels of serum glucose, triglycerides, cholesterol, high density lipoprotein (HDL) and liver enzymes were measured by routine laboratory kits. Results: Our findings demonstrate that this extract reduced weight in the group that received high-fat diet, at both doses (P<0.05). This extract also significantly decreased the levels of serum glucose, triglycerides, and cholesterol and increased HDL in the group that received high-fat diet (P<0.05) however it had no effect on reduction of liver enzymes. Conclusion: Our data suggest that the hydroalcoholic extract of Peganum harmala has beneficial effects on controlling body weight in animals fed with a high-fat diet and it also significantly improves biochemical parameters in animals fed with a high-fat diet.