Obesity is a metabolic disease characterized by an imbalance between caloric intake and expenditure, leading to excess fat and increasing the risk of various health conditions. This study compares the anti-obesity effects of gold nanoparticles (AuNPs) to orlistat in an experimental model of induced obesity in Wistar Albino rats. In addition to negative and positive control rats, obese rats were treated with variable daily and weekly doses of AuNPs and daily orlistat for nine weeks. Bioelectric impedance analysis (BIA) and dissection techniques were used to indirectly and directly measure body-composition in all rat groups. Hepatic and renal function and ultrastructure were assessed by blood biochemical and histological examinations to detect treatment-related alterations. High doses of AuNPs reduced body fat, increased muscle mass, improved dyslipidemia, glycemia, and antioxidant effects in obese rats, and restored normal TG, FBG, and MDA levels by reducing obesity-related oxidative damage. Histological and ultrastructural examinations showed that these high doses repaired liver and kidney cells, and reduced fat accumulation and body weight compared to the standard treatment for obesity by orlistat.