Adverse drug reactions are increasingly challenging in medical settings; either due to their high doses or prolonged use or due to the pharmacodynamics nature of the medications. Methotrexate found applications for different ailments making their adverse effects common. It's worth trying to prevent or mitigate these adverse effects of methotrexate using available remedies if any. We aimed to reduce the hepatotoxic effects of methotrexate using L-carnitine compared to N-acetylcysteine as a positive control. To do so, a group of rats were exposed to methotrexate alone or in combination with L-carnitine or N-acetyl cysteine. Liver biochemical parameters and histological architecture were identified and compared with negative and positive groups. The results confirmed that L-carnitine and N-acetyl cysteine mitigated hepatic tissue injury confirmed by biochemical analysis of liver enzymes and histological study. The present study confirms the hepatoprotective effect of L-carnitine as a protective substance to reduce the adverse side effects of chemotherapeutic agents that cause oxidative tissue injury concomitant with inflammation.