Obesity represents a major challenge to the pharmaceutical community due to the minimal availability of anti-obesity drugs and drawbacks of current weight-loss agents. The study was designed to evaluate the use of sage oil as a potential anti-obesity agent via its effect on different physiological, biochemical, and hormonal parameters in rats. Rats were divided into two groups: one group was continued on a standard commercial rodent diet and served as the non-obese control. The other group was fed a high-fat diet for seven weeks to prepare an obese rat model. Then, the obese rats were divided into three groups; one group remained without treatment as positive control, the other two groups received 100 mg/kg orally of the sage oil for 10 or 20 days. The results of the present study showed that treatment with sage oil significantly decreased rats' food intake, epididymal fat, and body weight, and improved their lipid profile levels; it also modulated the leptin resistance. This anti-obesity effect of sage oil was associated with the increased expression of adiponectin and decreased both of leptin and sterol regulatory element-binding protein (SREBP-1c) levels, and this effect may be mediated through AMPK activation. Additionally, the sage oil did not have any effects on the liver's integrity, as was proven by the non-altered ALT levels.