Appetite and metabolic control are the main factors controlling body weight gain and could be the keys for controlling the problem of obesity. Usnic acid (UA), an uncoupler of oxidative phosphorylation, was known for its use in many products to control body weight. It was reported to be hepatotoxic. Hence the aim of the present study was to test its safety dose using experimental rats. Forty adult male lean rats (200-250 g) were divided into four groups ten animals each (n=10); control received standard diet, group1 received 1% carboxymethyl cellulose water solution, group 2 received 100 mg usnic acid/kg and group 3 received 300 mg usnic acid/kg, 5 days for 7 weeks using gastric gavages. Serum glucose, liver functions, lipid profile, lipase, leptin and Insulin were estimated. Liver was processed for electron microscope studies and results were analyzed using SPSS. The liver index was increased significantly (P≤0.05) in high-dose usnic acid compared to the control. Hepatocytes showed an increase in lipid droplets, swollen mitochondria, fragmented rough endoplasmic reticulum cisterns, abundant smooth endoplasmic reticulum and focal damage of hepatocyte membranes near bile canaliculi, all these changes were dose dependent. There was significant increase in total protein, albumin and total bilirubin in group received low-dose of Usnic acid (P≤0.05). Glucose, magnesium, total protein, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and total bilirubin were significantly increased in group received Usnic acid at high-dose (P≤0.05). Serum cholesterol and high density lipoprotein were significantly increased in all treated groups (P≤0.05) while triglycerides were slightly increased. In conclusion, usnic acid in controlled low dose is potentially non hepatotoxic in lean rats and could be used safely in future weight loss products especially if formulated as adipocytes targeted nanoparticles.