The current study aims to investigate the rat hepatotoxicity caused by acetaminophen (APAP) which is the main factor for drug-induced liver failure. Although the precise mode with which APAP damages the liver is unknown, recent research has demonstrated that the enzyme cytochrome P450 is affected, resulting in increased metabolite production resulting in liver failure. In this study, rats were administered with 50mg/kg/b.w to induce hepatic damage and in contrast to damage, the hepatoprotective effects was ana- lyzed with various vitamins A, E, and C. The effects of vitamins A, E, and C were examined using general biochemical parameters, liver marker enzymes, hepatic antioxidants, inflammatory biomarkers, gene ex- pression, and histopathology assays. The results of this study indicate that through lowering ALT, AST, and ALP levels, all vitamins had hepatoprotective benefits against APAP-induced hepatoxicity. Vitamin E had the greatest impact when compared to vitamins A and C. Hence, we recommend that patients receiv- ing APAP treatment may take vitamin E as a supplement to minimize liver damage.