Albendazole (ABZ) and mebendazole (MBZ) are two benzimidazole-derived drugs that show remarkable antihelmintic activity and are widely used in the treatment and control of helminths. Some antihelmintic drugs seem to act through the deleterious generation of reactive oxygen and nitrogen species (ROS and RNS, respectively) to which helminths have no, or relatively low, antioxidant defences (AD), when compared to aerobic organisms. The main objective of the present study consisted of the evaluation of the effect of both drugs on the AD and on some oxidative stress indicators in the host liver. Adult, male, Wistar rats were treated with ABZ or MBZ at doses of 40 mg/kg for different periods of time (2, 4, 8 and 10 days). After treatment, the activities of superoxide dismutase, catalase, glutathione reductase, and glutathione S-transferase, as well as the concentrations of TBARS, reduced glutathione, oxidized glutathione and total glutathione, were evaluated in rat hepatocytes. The serum nitrogen monoxide, usually known as nitric oxide (NO) levels, was also measured. The results showed that both drugs provoked an oxidative stress condition, demonstrated through the elevation of TBARS contents and through the decrease of some AD. Moreover, ABZ showed to be a strong ROS and RNS generator while MBZ showed a low and transient effect on ROS generation. It is suggested that MBZ could be the first-choice drug in the treatment of helminthiasis because it shares a similar therapeutic indication with ABZ, and because it causes only a mild oxidative stress to the host.