Background and purpose: Hepatotoxicity from frequently prescribed drugs has become an evolving health problem. This study was conducted to evaluate the risk of acute and chronic administration of acetaminophen (AAP), ibuprofen (Ibu), and acetylsalicylic acid (ASA). Methods: One hundred and twenty male albino rats, were divided into 2 main groups for acute and chronic study. Each group was sub-classified into 5 sub-groups (12 rats for each). Acute study: control (normal saline), AAP (single oral dose, 540 mg/kg, bw), AAP +Zn (APP and Zn ,227 mg/liter drinking water 24 hours before AAP administration), Ibu (single oral dose,440 mg/kg, bw), and ASA (single intraperitoneal dose,540 mg/kg, bw). Chronic (period for 60 days): control (normal saline), AAP (single daily doses, 48 mg/kg, bw), AAP +Zn (APP and Zn, 227 mg/liter drinking water for 6o days), Ibu (single daily doses, 48 mg/kg, bw), and ASA (single daily intraperitoneal doses, 40 mg/kg,). Results: Hepatic aminotransferases, alkaline phosphatase, isocitrate dehydrogenase, serum glycosaminoglycans, tissue hydroxyproline, and malondialdehyde were significantly elevated, but glutathione was significantly decreased, in both acute and chronic treatments in all treated groups. Prior treatment with Zn couldn't change the effects of AAP, except on oxidative stress. Tissue changes after chronic treatment varied from fatty changes to vascular congestions and inflammation. Conclusion: We assume that both acute and chronic administration of AAP, Ibu, and ASA have deleterious hepatotoxic and fibrogenic effects on the liver with a non-significant protective role to Zn co-administration with AAP against oxidative stress.