Recently, great consideration has been rewarded to Cannabis-and Pregabalin because of the important role of their uses, their presence in food, oil, and fiber for humans and animals, and therapeutics also for their addiction effects. The present study pointed to scrutinizing oxidative stress and histopathological changes in the liver of rats caused by cannabis as well as Pregabalin. In this study, Thirty Wistar male mice were clustered into three groups. The first group was kept as a negative control, the second group was the cannabis group (administered Cannabis by gastric tube at a dose of 3 mg/kg b.wt.) and the third group was the pregabalin group, (administered pregabalin by gastric tube on a dosage of 30 mg/kg b.wt.) every day for eight weeks. Oxidative stress parameters (MDA and GSH) were done and analyzed in serum. A histopathological examination of the liver sections was done. Results revealed that the cannabis cluster showed a significant increase while pregabalin showed a significant decrease in MDA activity compared with the control cluster; whereas Cannabis resulted in a substantial reduction in the level of GSH while, pregabalin showed a substantial increase in GSH level compared with the control group. Along with this, there were some pathological changes in liver tissue.