Linezolid has a better choice for eradication of methicillin-resistant Staphylococcus aureus (MRSA) infections, but its use is limited because of linezolid-induced hepatotoxicity, myelosuppression, and lactic acidosis. This research elucidated the role of silymarin against hepatoxicity of linezolid therapy in MRSA infected Wistar rats. The rats were rendered neutropenic by an intraperitoneal injection of cyclophosphamide injection. The neutropenic rats were injected subcutaneously with 10⁶ CFU/ml of MRSA. The rats were divided into 6 groups. Normal control, Infected, Infected animals treated with linezolid 50 mg/kg/twice/day and Infected animals treated with linezolid and different dose of silymarin 25, 50, and 100 mg/kg/twice/day for 14 days. On the 15th day, the blood, liver, kidney, and bone marrow were collected for biochemical and histopathological examination. The MRSA was confirmed by PCR assay. The minimum inhibitory concentration of linezolid was 0.5–2 μg/ml. The linezolid induced liver damage was confirmed by elevation of marker enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), Lactate dehydrogenase (LDH) levels, serum bilirubin, lactate, and histopathological studies of the liver. The linezolid treated rats also showed myelosuppression, lactic acidosis, oxidative stress and decreased intestinal alkaline phosphatase (IAP). The silymarin administration exhibited marked hepatoprotective effect by significantly lowering the liver marker enzymes, serum parameters, and cytological findings reflect the hepatoprotection. Additionally, Silymarin showed protection against myelosuppression and lactic acidosis evidenced by bone marrow smear and serum lactate estimation. Antioxidant effect of silymarin was confirmed by decreased levels of lipid peroxidation, restored the enzymatic and non-enzymatic antioxidants of the liver nearer to normal. The present study indicates that the silymarin could be a better herbal therapeutic agent which protects against the linezolid induced hepatotoxicity in MRSA infected rats.