Intoxication with ranitidine is considered as one of the major causes of hepatotoxicity. The current study aimed to investigate the protective effect of an ethanolic extract from Azolla pinnate (APE) against ranitidine -induced hepatotoxicity in rats. The present study was carried out on 40 male Wister albino rats, which were randomly divided into four groups (n=10). The 1st group, control group; orally administered saline. The second group, was given ranitidine (150 mg/kg body weight (BW) orally for 30 days); The third group, orally administered APE (10 mg/kg BW), daily for 30 days;The fourth group, was orally administrated ranitidine (as group 2), and APE (as group 3) together for 30 days. At the end of the experiment samples from blood and liver were obtained. Ranitidine increased serum activities of alanine and aspartate aminotransferases and serum levels of urea, creatinine, tumor necrosis factor alpha and interleukin-1β and hepatic tissue malondialdehyde contents. However, it decreased serum levels of interleukin-10 and GSH contents and catalase and superoxide dismutase activities in hepatic tissue. On the contrast, administration of rats with APE ameliorated ranitidine-induced alterations in liver function and structure stating the benefits of Azolla's phytochemical contents. Therefore, A. pinnate extract is a potential protective against ranitidine-induced hepatotoxicity via its antioxidant (presence of tamarixetin, rutin and quercetin) anti-inflammatory and anti-apoptotic activities.