Tramadol is a synthetic opioid analgesic commonly prescribed for moderate to severe pain. This study was designed to evaluate the effects of silymarin supplementation on Tramadol induce injury, oxidative stress, and PCNA expression alterations on the liver in rats. For this purpose 40 male albino rats were divided into four groups and treated for 4 weeks (group 1 controlled, group 2 was silymarin, group 3 was Tramadol, and group 4 was Tramadol plus silymarin). The obtained results revealed that; serum GPT, GOT, ALP, GGT activities and MDA levels in liver tissues were significantly increased in rats treated with Tramadol as compared to the control group while, total protein, albumin, globulin levels in serum, GSH, SOD, and catalase levels in liver tissues levels were significantly decreased in Tramadol group when compared with control rats. Liver sections in rats treated with Tramadol exhibited mild positive reactions were detected for PCNA-ir, marked dilation or congestion in central veins, marked cellular infiltrations, atrophied and vacuolated hepatocytes. Treated rats with Tramadol plus silymarin succeeded to modulate these observed abnormalities resulting from Tramadol as indicated by the reduction of enzyme activity and the pronounced improvement of the investigated biochemical, antioxidant parameters, oxidative stress, hepatic injury, and PCNA alterations. Further studies are needed to investigate the impacts of tramadol on human health.