Methotrexate (MTX) is an important drug for rheumatic and non-rheumatic disease therapy. MTX has been associated with many adverse effects ranging from asymptomatic transaminase elevation to fibrotic tissue formation and fatal hepatic necrosis due to oxidative stress. Concerns regarding potential liver toxicity have led to the avoidance of medication, termination, or advice for inquiries in clinical care. The protective and therapeutic effects of a new generation anti-angina drug, ranolazine (RAN), on MTX-induced liver damage were investigated by evaluating its antioxidant mechanism in rats. Thirty-two female Wistar Albino rats were randomly assigned to Control, RAN, prophylaxis, and treatment groups (n=8/group). Liver function enzymes, histopathological assessment and serum biochemical parameters were examined. Malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) were also measured in liver tissue. MTX administration caused mononuclear inflammation, vascular congestion, ductal proliferation, vacuolization, and fibrosis as evaluated using Roening grading and increases in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and lactate dehydrogenase levels ( p<0.05) in the blood, which is compatible with hepatocyte damage in the blood and increased MDA levels in the tissue. Histopathologically, vascular congestion and ductal proliferation, and biochemically, MDA and SOD levels and serum biochemical parameters, significantly decreased in the RAN+MTX and MTX+RAN groups ( p<0.001) when compared with the MTX group. No significant changes were observed in terms of SOD and GSH levels and fibrosis scores in RAN-administered groups ( p>0.05). According to our results, RAN may be a potential hepatoprotective agent against MTX-induced liver injury.