Aim: The present study was conducted to investigate the protective effect of chamomile flowers methanolic extract (CFME) and fennel seeds methanolic extract (FSME) on azathioprine (AZA), an immunosuppressant drug, which induced a liver injury and oxidative stress in rats. Methods: Rats were divided into 6 groups (8 rats each) and treated orally for 28 consecutive days as follows. Group 1: rats were given normal saline and used as controls; group 2: rats treated with CFME (200 mg/kg); group 3: rats treated with FSME (200 mg/kg); group 4: rats treated with AZA (25 mg/kg); and groups 5 and 6: rats treated with CFME (200 mg/kg) or FSME (200 mg/kg) 15 min prior to AZA (25 mg/kg) treatment. At the end of experimental period, blood and liver samples were collected from all groups for biochemical analysis and histological examination. Results: The obtained data revealed that AZA-induced hepatic injury in the rats as evidenced by the significant increase in serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, cholesterol, and direct bilirubin as well as hepatic malondialdehyde level accompanied with significant decrease in reduced glutathione content and total antioxidant capacity in the liver. Moreover, body weight gain showed the significant decrease and relative liver weight showed the significant increase on AZA treatment. The sequential significant changes in biochemical parameters were accompanied by severe histological changes in the liver tissue, including hepatocytes disorganization with pyknotic nuclei, fatty degeneration, congestion, fibrosis, and bile duct necrosis around the portal tract. The areas of hemorrhages in blood vessels and in between hepatocytes were also seen. However, the results showed the potential hepatoprotective effects of CFME and FSME against AZA-induced liver injury and oxidative stress. They succeeded in restoring the biochemical parameters and improving the histological picture of the liver. This improvement was more pronounced in the rats pretreated wi...