Introduction: Diclofenac (DIC) is one of the compounds derived from acetic acid which is known for its anti-inflammatory and analgesic attributes. Silymarin is a flavonoid compound which is derivate from Silybum marianum seeds. This research was done to assess the protective role of silymarin against liver toxicity induced by DIC in male rats. Methods: Randomly, 40 male Wistar rats were assigned into five groups as follows: Group 1: control group, Group 2: DIC-only treated (50 mg/kg, i. p), Group 3: silymarin-only treated (200 mg/kg, p. o); Groups 4 and 5: DIC (50 mg/kg, i. p) plus silymarin (100 mg/kg and 200 mg/kg, p. o, respectively) treated. Various biochemical, molecular, and histological parameters were evaluated in serum and tissue. Results: In the DIC-only treated group, the levels of liver glutathione peroxidase (GPx), superoxide dismutase (SOD), intracellular glutathione (GSH) and catalase (CAT) significantly diminished and the levels of total bilirubin, alkaline phosphatase (ALP), nitrite, alanine aminotransferase (ALT), malondialdehyde (MDA), serum tumor necrosis factor-α (TNF-α ), aspartate aminotransferase (AST), and TNF-α gene expression were remarkably elevated relative to control animals. In other hands, treatment with silymarin caused a noticeable elevation in GPx, SOD, GSH, CAT and a remarkable reduction in levels of total bilirubin, ALP, nitrite content, ALT, MDA, serum TNF-α , AST and TNF-α gene expression relative to DIC-only treated group. Histopathological injuries were also improved by silymarin administration. Conclusion: The results confirm that silymarin has an ameliorative effect on liver toxicity induced by DIC and oxidative stress in male rats.